KR20180086188A - 암을 예방 또는 치료하기 위한 방법 및 조성물 - Google Patents
암을 예방 또는 치료하기 위한 방법 및 조성물 Download PDFInfo
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- KR20180086188A KR20180086188A KR1020187012840A KR20187012840A KR20180086188A KR 20180086188 A KR20180086188 A KR 20180086188A KR 1020187012840 A KR1020187012840 A KR 1020187012840A KR 20187012840 A KR20187012840 A KR 20187012840A KR 20180086188 A KR20180086188 A KR 20180086188A
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Abstract
본 개시내용은 코끼리 p53을 암호화하는 핵산 서열 또는 코끼리 p53 아미노산 서열을 사용하는 암 세포를 저해하기 위한 방법 및 조성물을 지시한다.
Description
관련 출원(들)의 교차 참조
본 출원은 2015년 10월 8일에 출원된 미국 가출원 특허 번호 62/239,103 및 2016년 8월 24일에 출원된 미국 가출원 특허 번호 62/379,179에 대한 우선권을 주장하고, 이들의 전문은 본원에 참조로서 완전히 포함된다.
전자 제출된 서류의 참조 인용
이와 동시에 제출되고 다음과 같이 확인된 컴퓨터-판독가능한 뉴클레오티드/아미노산 서열 목록이 본원에 참조로서 완전히 포함된다: One 184,774 bytes ASCII (Text) file named "026389-9173_ST25.txt" created on October 6, 2016.
발명의 배경
다세포 유기체는 돌연변이 및 암의 발병에 대항하여 보호하기 위해 내인성 방어를 갖는다. 하나의 이러한 방어 기전은 종양 단백질 p53(유전자 TP53에 의해 암호화됨)에 의해 조절된 신호전달 경로이고, 이는 암의 중요한 억제제이다. "게놈의 가디언(guardian)"으로 언급되는 p53은, DNA 손상이 감지되고 돌연변이의 교정을 개시하거나 손상이 회복할 수 없는 경우 아폽토시스를 촉발할 때에, 세포 분열을 중단시킬 수 있다[참조: Blagosklonny. Int J Cancer, 98: 161-166(2002)]. 사람은 TP53의 하나의 카피(2개의 대립유전자)를 포함하고, 둘 다의 기능성 대립유전자는 암 발병을 예방하는데 중요하다. 심지어 하나의 기능적 대립유전자의 부재는 리-프라우메니 증후군(LFS), 암 소인을 야기하고, 여기서, 환자는 그들의 일생 동안 암 발병이 90% 변화한다[참조: McBride et al. Nat Rev Clin Oncol; 11(5): 260-271 (2014)]. p53의 불활성화는 또한 암을 야기할 수 있고[참조: Lane, DP. Nature; 358(6381): 15-16 (2014); Hanahan et al. Cell; 144(5): 646-674 (2011)], 사람에서 p53 기능은 자연적으로 연령에 따라 감소하고[참조: Feng et al., PNAS; 104(42): 16633-16638 (2007)], 모든 남성의 절반 및 모든 여성의 3분의 일에서 그들의 일생 동안 암이 발병할 수 있다[참조: American Cancer Society; Cancer Facts & Figures (2015)]. p53의 돌연변이는 다수의 사람 암에서 확인되었다[참조: Hollstein et al., Science; 253(5015): 49-53 (1991)].
조사자는 자연스럽게 p53의 보호 특성을 이용하여 암을 퇴치하는데 초점을 맞췄다. 예를 들면, 레트로바이러스- 및 아데노바이러스-매개된 TP53-유전자 요법은 사람 p53을 암 세포에 전달하기 위해 발달되었고[참조: Cai et al. Hum Gene Ther: 4: 617-624 (1993); Brandt et al. Am J Epidemiol; 90: 484-500 (1969)], p53의 축적이 마우스 더블 미뉴트 2(MDM2; mouse double minute 2)에 의해 음성 조절을 방해하여 유도될 수 있다[참조: Vassilev et al. Science; 3i03: 844-848 (2004)]. 그러나 이들 요법은 주로 사람에서 야생형 p53의 활성을 복원하거나, 돌연변이 p53으로 암 세포를 제거하는데 초점을 맞춘다.
각각의 세포 분열이 잠재적으로 새로운 유전 돌연변이를 도입할 수 있음을 고려할 때, 더 큰 유기체(자연적으로 더 큰 수의 세포 분열을 필요로 함)에서 돌연변이된 세포의 수가 증가할 것임이 본래 의심된다[참조: Tomasetti et al., Science; 347(6217): 78-81 (2015)]. 모든 포유류 세포가 종양형성 돌연변이에 동등하게 감수성인 경우, 암 위험은 신체 크기(세포의 수) 및 종 수명(세포 분열의 수)에 따라 증가하여야 한다. 그러나 이러한 이론은 35년 전에 틀렸음이 입증되었는데, 동물에 걸쳐서 암 발생정도가 더 큰 신체 크기 및 수명 때문에 증가하지 않는 것으로 나타났기 때문이다[참조: Caulin et al., Trends Ecol Evolut; 26(4): 175-182 (2011); Peto et al., Br J Cancer; 32(4): 411-426 (1975)]. 암에 대한 이러한 저항의 세포 및 분자 기전은 더 큰 동물에서 명백하게 이해되지 않지만, 그러나 최근 연구는 코끼리가 특히 암 발병에 저항성인 것으로 나타났다[참조: Abegglen et al. JAMA; 314(17): 1850-60 (2015)]. 또한 코끼리가 TP53 유전자의 추가(extra) 카피를 갖는 것으로 밝혀졌다. 추적조사 연구에서 코끼리 p53(EP53)은, 심지어 암 세포가 이미 사람 p53을 포함하는 경우에도 암 세포 사멸에 특히 효과적인 것으로 나타났다.
보다 효과적으로 암성 세포에 대한 p53 기능을 회복시키기 위한 조성물 및 방법이 여전히 요구된다. 본 발명은 이러한 조성물 및 방법을 제공한다.
발명의 간단한 요지
본 개시내용은 암 세포를 (a) 코끼리 p53 단백질을 각각 암호화하는 하나 이상의 핵산 서열, 또는 (b) 하나 이상의 코끼리 p53 단백질과 접촉시킴을 포함하고, 이에 의해 암이 저해되는, 암의 저해 방법을 제공한다.
본 개시내용은 또한 약제학적으로 허용되는 담체 및 (a) 코끼리 p53 단백질을 각각 암호화하는 하나 이상의 핵산 서열 또는 (b) 하나 이상의 코끼리 p53 단백질를 포함하는 조성물을 제공한다.
도 1은 종양을 나타낸 각각의 종에서 수행된 부검의 백분율과 비교하여 33 상이한 포유류 종의 로그(질량(mass) x 수명)의 플롯이다.
도 2는 아프리카 코끼리에서 그룹 A 및 그룹 B TP53 레트로유전자를 나타내는 계통수이다.
도 3A는 아프리카 및 아시아 코끼리로부터의 PBMC 및 아프리카 코끼리 섬유아세포에서 수행된 TP53-특이적인 RT-PCR의 결과를 나타내는 전기영동 겔의 영상이다. 201bp 및 185bp에서의 2개의 대역을 나타내고, 이는 코끼리 p53 레트로유전자의 그룹 A 및 그룹 B와 상호관련된다. 도 3B는 3A에 도시된 PCR 결과의 더 높은 해상도 영상이다.
도 4A 및 4B는 EP53 레트로유전자로 형질감염된 HEK293 세포가 MG132 또는 독소루비신에 의해 유도된 DNA 손상에 반응하여 단백질의 발현을 증가시킴을 나타내는 웨스턴 블롯의 영상이다. 도 4C는 EP53r9로 형질감염된 HEK293 세포가 이온화 방사선으로부터의 DNA 손상에 반응하여 단백질을 상향조절하고, 인산화된 단백질의 발현을 증가시킬 수 있음을 나타내는 웨스턴 블롯의 영상이다.
도 5A는 2 Gy 및 6 Gy 이온화 방사선에 반응하여 후기 아폽토시스를 겪은 사람 말초 혈액 림프구와 비교하여 코끼리 말초 혈액 림프구의 백분율을 나타내는 막대 그래프이다. 도 5B는 2 Gy 및 6 Gy 이온화 방사선에 반응하여 조기 아폽토시스를 겪은 사람 말초 혈액 림프구와 비교하여 코끼리 말초 혈액 림프구의 백분율을 나타내는 막대 그래프이다.
도 6A는 아프리카 코끼리로부터의 림프구가 독소루비신에 노출 후 더 높은 수준의 후기 아폽토시스를 나타내는 막대 그래프이다. 도 6B은 아프리카 코끼리로부터의 림프구가 독소루비신에 노출 후 더 높은 수준의 조기 아폽토시스를 나타내는 막대 그래프이다.
도 7은 리-프라우메니 증후군을 갖는 환자, 10 건강한 대조군, 및 1 아프리카 코끼리로부터의, 2 Gy 이온화 방사선에 노출 후 후기 아폽토시스를 겪은 말초 혈액 림프구의 백분율을 나타내는 산포도이다.
도 8은 코끼리 섬유아세포가 독소루비신에 노출 후 사람 섬유아세포 보다 더 큰 카스파제 3/7 절단을 나타내는 선 그래프이다.
도 9는 2 Gy 및 6 Gy 이온화 방사선 후 5시간 및 24시간에 p53 및 p21 단백질 발현의 증가는 나타내는 웨스턴 블롯의 영상이다.
도 10A은 2 Gy 이온화 방사선 치료 후 18시간에 사람 및 아시아 코끼리로부터의 림프구에서 아폽토시스 세포의 백분율을 나타내는 막대 그래프이다. 도 10B는 2 Gy 이온화 방사선 후 5시간에 아시아 코끼리 림프구에서 p21 단백질 발현을 나타내는 웨스턴 블롯의 영상이다. 도 10C는 이온화 방사선 치료 후 18시간에 연령 그룹으로 분류된 아시아 코끼리에서 아폽토시스 림프구의 백분율을 나타내는 막대 그래프이다.
도 11A은 독소루비신으로 치료 후 EP53r5로 형질감염된 NIH 3T3 세포에서 카스파제 활성이 증가됨을 나타내는 선 그래프이다. 도 11B는 독소루비신으로 치료 후 EP53r9로 형질감염된 NIH 3T3 세포에서 카스파제 활성이 증가됨을 나타내는 선 그래프이다.
도 12A는 독소루비신으로 치료 후 EP53r6으로 형질감염된 U-2OS 세포에서 카스파제 활성이 증가됨을 나타내는 선 그래프이다. 도 12B는 독소루비신으로 치료 후 EP53anc로 유도된 U-2OS 세포에서 카스파제 활성이 증가됨을 나타내는 선 그래프이다. 도 12C는 DNA 손상을 유도하기 위해 EP53anc로 유도되고 독소루비신으로 치료된 U-2OS 세포가 p53 표적 유전자, p21 및 MDM2의 증가는 나타내는 것을 보여주는 웨스턴 블롯의 영상이다.
도 13은 GFP-표지된 EP53r9로 형질감염된 U-2OS 세포가 인산화된-EP53r9의 증가를 나타내고 인산화된-사람 P53의 감소가 수반되는 것을 보여주는 웨스턴 블롯이다.
도 14A는 EP53r9로 형질감염된 HCT 116 세포가 독소루비신으로 치료 후 카스파제 활성의 증가를 나타냄을 보여주는 점 도표이다. 도 14B는 EP53r9로 형질감염된 HCT 116 세포가 EP53r9 발현의 증가를 나타내는 웨스턴 블롯을 보여주고, 이는 독시사이클린의 용량 증가와 상호관련된다.
도 2는 아프리카 코끼리에서 그룹 A 및 그룹 B TP53 레트로유전자를 나타내는 계통수이다.
도 3A는 아프리카 및 아시아 코끼리로부터의 PBMC 및 아프리카 코끼리 섬유아세포에서 수행된 TP53-특이적인 RT-PCR의 결과를 나타내는 전기영동 겔의 영상이다. 201bp 및 185bp에서의 2개의 대역을 나타내고, 이는 코끼리 p53 레트로유전자의 그룹 A 및 그룹 B와 상호관련된다. 도 3B는 3A에 도시된 PCR 결과의 더 높은 해상도 영상이다.
도 4A 및 4B는 EP53 레트로유전자로 형질감염된 HEK293 세포가 MG132 또는 독소루비신에 의해 유도된 DNA 손상에 반응하여 단백질의 발현을 증가시킴을 나타내는 웨스턴 블롯의 영상이다. 도 4C는 EP53r9로 형질감염된 HEK293 세포가 이온화 방사선으로부터의 DNA 손상에 반응하여 단백질을 상향조절하고, 인산화된 단백질의 발현을 증가시킬 수 있음을 나타내는 웨스턴 블롯의 영상이다.
도 5A는 2 Gy 및 6 Gy 이온화 방사선에 반응하여 후기 아폽토시스를 겪은 사람 말초 혈액 림프구와 비교하여 코끼리 말초 혈액 림프구의 백분율을 나타내는 막대 그래프이다. 도 5B는 2 Gy 및 6 Gy 이온화 방사선에 반응하여 조기 아폽토시스를 겪은 사람 말초 혈액 림프구와 비교하여 코끼리 말초 혈액 림프구의 백분율을 나타내는 막대 그래프이다.
도 6A는 아프리카 코끼리로부터의 림프구가 독소루비신에 노출 후 더 높은 수준의 후기 아폽토시스를 나타내는 막대 그래프이다. 도 6B은 아프리카 코끼리로부터의 림프구가 독소루비신에 노출 후 더 높은 수준의 조기 아폽토시스를 나타내는 막대 그래프이다.
도 7은 리-프라우메니 증후군을 갖는 환자, 10 건강한 대조군, 및 1 아프리카 코끼리로부터의, 2 Gy 이온화 방사선에 노출 후 후기 아폽토시스를 겪은 말초 혈액 림프구의 백분율을 나타내는 산포도이다.
도 8은 코끼리 섬유아세포가 독소루비신에 노출 후 사람 섬유아세포 보다 더 큰 카스파제 3/7 절단을 나타내는 선 그래프이다.
도 9는 2 Gy 및 6 Gy 이온화 방사선 후 5시간 및 24시간에 p53 및 p21 단백질 발현의 증가는 나타내는 웨스턴 블롯의 영상이다.
도 10A은 2 Gy 이온화 방사선 치료 후 18시간에 사람 및 아시아 코끼리로부터의 림프구에서 아폽토시스 세포의 백분율을 나타내는 막대 그래프이다. 도 10B는 2 Gy 이온화 방사선 후 5시간에 아시아 코끼리 림프구에서 p21 단백질 발현을 나타내는 웨스턴 블롯의 영상이다. 도 10C는 이온화 방사선 치료 후 18시간에 연령 그룹으로 분류된 아시아 코끼리에서 아폽토시스 림프구의 백분율을 나타내는 막대 그래프이다.
도 11A은 독소루비신으로 치료 후 EP53r5로 형질감염된 NIH 3T3 세포에서 카스파제 활성이 증가됨을 나타내는 선 그래프이다. 도 11B는 독소루비신으로 치료 후 EP53r9로 형질감염된 NIH 3T3 세포에서 카스파제 활성이 증가됨을 나타내는 선 그래프이다.
도 12A는 독소루비신으로 치료 후 EP53r6으로 형질감염된 U-2OS 세포에서 카스파제 활성이 증가됨을 나타내는 선 그래프이다. 도 12B는 독소루비신으로 치료 후 EP53anc로 유도된 U-2OS 세포에서 카스파제 활성이 증가됨을 나타내는 선 그래프이다. 도 12C는 DNA 손상을 유도하기 위해 EP53anc로 유도되고 독소루비신으로 치료된 U-2OS 세포가 p53 표적 유전자, p21 및 MDM2의 증가는 나타내는 것을 보여주는 웨스턴 블롯의 영상이다.
도 13은 GFP-표지된 EP53r9로 형질감염된 U-2OS 세포가 인산화된-EP53r9의 증가를 나타내고 인산화된-사람 P53의 감소가 수반되는 것을 보여주는 웨스턴 블롯이다.
도 14A는 EP53r9로 형질감염된 HCT 116 세포가 독소루비신으로 치료 후 카스파제 활성의 증가를 나타냄을 보여주는 점 도표이다. 도 14B는 EP53r9로 형질감염된 HCT 116 세포가 EP53r9 발현의 증가를 나타내는 웨스턴 블롯을 보여주고, 이는 독시사이클린의 용량 증가와 상호관련된다.
발명의 상세한 설명
본 개시내용은, 적어도 부분적으로, 아프리카 코끼리가 사람 보다 암에 더 큰 저항성(resistant)이 있다는 발견에 근거를 둔다. 암 사망율은 사람의 약 11% 내지 25%에서 발생하는 반면, 코끼리의 약 3% 내지 6%에서 암이 발생한다. 암에 대한 이러한 증가된 저항성은 부분적으로 p53 단백질을 암호화하는 코끼리에서 TP53 유전자의 유전 카피의 증가로 설명될 수 있다. 사람만이 하나의 카피의 TP53(2 대립유전자)를 갖는 반면, 코끼리는 적어도 20 카피(40 대립유전자)의 코끼리 p53 (EP53) 유전자를 갖는다. 세포 배양 연구에서, 코끼리 림프구가 이온화 방사선 노출로부터 DNA 손상에 반응하여 아폽토시스를 실행할 가능성이 더 많은 것으로 발견되었고, 이는 코끼리 p53-매개된 아폽토시스가 촉발되기 전에 DNA 손상에 대한 더 낮은 역치(threshold)를 제시한다. 코끼리 p53은 DNA 손상을 검출하고 유기체로부터 돌연변이된 세포를 제거할 때 사람 p53 보다 더 효과적인 것으로 나타난다. 코끼리 p53의 사용은 이전에 사람 암을 표적화하기 위한 기전으로서 조사되지 않았다.
코끼리 p53 서열
본 개시내용은 암의 저해 방법을 제공하고, 상기 방법은 암 세포를, 코끼리 p53 단백질을 각각 암호화하는 하나 이상의 핵산 서열, 또는 하나 이상의 코끼리 p53 단백질과 접촉시킴을 포함한다.
핵산은 단일 가닥 또는 이중 가닥일 수 있거나, 이중 가닥 및 단일 가닥 서열 둘 다의 부분을 포함할 수 있다. 핵산은 DNA일 수 있고, 데옥시리보뉴클레오티드, 또는 RNA를 포함하고, 리보뉴클레오티드를 포함한다. 핵산은 화학적 합성 방법으로 또는 재조합 방법으로 수득될 수 있다. 특정한 핵산 서열은 이의 보존적 변형된 변종(conservatively modified variants)(예를 들면, 코돈 치환), 대립유전자, 오솔로그(orthologs), 단일 뉴클레오티드 다형태(SNPs), 및 상보적 서열 뿐만 아니라 상기 명확하게 나타낸 서열을 포함할 수 있다.
암 세포는 코끼리 p53 단백질을 암호화하는 임의의 적합한 핵산 서열과 임의의 적합한 조합으로 접촉할 수 있다. 예를 들면, 일부 양태에서, 암 세포는 코끼리 p53 단백질을 암호화하는 하나의 핵산 서열과 접촉할 수 있다. 다른 양태에서, 암 세포를, 코끼리 p53 단백질을 각각 암호화하는 다수의 핵산 서열과 접촉시킨다. 코끼리가 적어도 20 카피의 TP53 유전자를 포함하기 때문에, 암 세포는 2 내지 25 핵산 서열(예를 들면, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 또는 25 핵산 서열)과 접촉할 수 있고, 이들 각각은 코끼리 p53 단백질을 암호화한다. 하나의 양태에서, 코끼리 p53 단백질을 암호화하는 하나 이상의 핵산 서열은 레트로유전자이다. 본원에 사용된 용어 "레트로유전자"는 역 전사에 의해 게놈 내로 백 카피(copied back)된 DNA 유전자로부터 전사된 RNA를 언급한다. 레트로유전자는 인트론이 결핍될 수 있다. 암 세포는 다수의 핵산 서열과 접촉할 수 있고, 이들 각각은 동일한 레트로유전자, 다수의 상이한 레트로유전자, 또는 이의 조합을 포함한다. 추가로 또는 대안적으로, 코끼리 p53 단백질을 암호화하는 핵산 서열은 선조 유전자일 수 있다. 본원에 사용된 용어 "선조 유전자"는 동계의(a family of) 유전자가 내려가는 공통 유전자를 언급한다. 선조 유전자는 선조 유전자 부활(resurrection) 또는 선조 유전자 복원으로부터 유래될 수 있고, 여기서, 선조 단백질은 계통발생학적 방법 및 단백질이 합성되는 DNA 분자 코딩으로 추론된다[참조: Chang et al., Integr Comp Biol; 43(4): 500-507 (2003)]. 암 세포는 다수의 핵산 서열과 접촉할 수 있고, 이들 각각은 동일한 선조 유전자, 다수의 상이한 선조 유전자, 또는 이의 조합을 포함한다. 다른 양태에서, 암 세포는 하나 이상의 p53-암호화 레트로유전자 및 하나 이상의 p53-암호화 선조 유전자의 조합과 접촉할 수 있다.
코끼리 p53 단백질을 암호화하는 레트로유전자의 핵산 서열의 예는, 이에 제한되는 것을 아니지만, 서열 번호 4, 서열 번호 6, 서열 번호 8, 서열 번호 10, 서열 번호 12, 서열 번호 14, 서열 번호 16, 서열 번호 18, 서열 번호 20, 서열 번호 22, 서열 번호 24, 서열 번호 26, 서열 번호 28, 서열 번호 30, 서열 번호 32, 서열 번호 34, 서열 번호 36, 서열 번호 38, 서열 번호 40, 서열 번호 42, 서열 번호 44, 서열 번호 46, 서열 번호 48, 서열 번호 50, 서열 번호 52, 서열 번호 54, 서열 번호 56, 서열 번호 58, 서열 번호 60, 서열 번호 62, 서열 번호 64, 서열 번호 66, 서열 번호 68, 서열 번호 70, 서열 번호 72, 서열 번호 74, 및 서열 번호 76을 포함한다. 코끼리 p53 단백질을 암호화하는 선조 유전자의 핵산 서열의 예는, 이에 제한되는 것을 아니지만, 서열 번호 2를 포함한다.
세포(예를 들면, 암 세포)로의 전달을 위해, 하나 이상의 핵산 서열은 유전자 전달 벡터 내로 도입될 수 있다. "유전자 전달 벡터(gene transfer vector)" 또는 "벡터"는 유전 물질(예를 들면, 핵산 서열)을, 적합한 숙주 세포 내로 운반할 수 있는 능력을 갖는 임의의 분자 또는 조성물이고, 여기서, 암호화된 단백질의 합성이 일어난다. 적합한 벡터는, 이에 제한되는 것을 아니지만, 플라스미드, 바이러스 벡터, 리포솜, 지질, 중합체, 무기 나노입자, 또는 상기한 것들의 임의의 조합을 포함하는 키메라 벡터(예를 들면, 플라스미드-지질 복합물 또는 플라스미드-중합체 복합물)를 포함한다. 적합한 바이러스 벡터는, 예를 들면, 레트로바이러스 벡터, 단순헤르페스 바이러스(HSV)-기반 벡터, 파르보바이러스-기반 벡터, 센다이 바이러스(SeV)-기반 벡터, 아데노-관련 바이러스(AAV)-기반 벡터, AAV-아데노바이러스 키메라 벡터, 및 아데노바이러스-기반 벡터를 포함하고, 예를 들면, 문헌[참조: Sambrook et al., Molecular Cloning, a Laboratory Manual, 4th edition, Cold Spring Harbor Press, Cold Spring Harbor, N.Y. (2012), 및 Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates and John Wiley & Sons, New York, N.Y. (2016)]에 기재된 표준 재조합 DNA 기술을 사용하여 제조할 수 있다. 적합한 중합체, 지질, 및 무기 나노입자는, 예를 들면, 문헌[참조: Peer et al., Nature Nanotechnology, 2:751-760 (2007), and Boussif et al., Proceedings of the National Academy of Sciences of the United States of America, 92: 7297-7301 (1995)]에 기재되어 있다.
다른 양태에서, 암 세포는 하나 이상의 코끼리 p53 단백질과 접촉할 수 있다. 암 세포는 임의의 적합한 코끼리 p53 단백질과 임의의 적합한 조합으로 접촉할 수 있다. 상기 논의한 바와 같이, 코끼리가 적어도 20 카피의 TP53 유전자를 포함하기 때문에, 암 세포는 2 내지 25 p53 단백질(예를 들면, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 또는 25 단백질)과 접촉할 수 있다. 하나 이상의 코끼리 p53 단백질은 하나 이상의 레트로유전자, 예를 들면, 본원에 기재된 것들로 암호화될 수 있다. 예를 들면, 암 세포는 다중 단백질과 접촉할 수 있고, 이들 각각은 동일한 레트로유전자, 다수의 상이한 레트로유전자, 또는 이의 조합으로 암호화된다. 추가로 또는 대안적으로, 하나 이상의 코끼리 p53 단백질은 선조 유전자, 예를 들면, 본원에 기재된 것들로 암호화될 수 있다. 암 세포는 다중 p53 단백질과 접촉할 수 있고, 이들 각각은 동일한 선조 유전자, 다수의 상이한 선조 유전자, 또는 이의 조합으로 암호화된다. 다른 양태에서, 암 세포는 하나 이상의 레트로유전자-암호화된 p53 단백질 및 하나 이상의 선조 유전자-암호화된 p53 단백질의 조합과 접촉할 수 있다.
레트로유전자-암호화된 코끼리 p53 아미노산 서열의 예는, 이에 제한되는 것을 아니지만, 서열 번호 5, 서열 번호 7, 서열 번호 9, 서열 번호 11, 서열 번호 13, 서열 번호 15, 서열 번호 17, 서열 번호 19, 서열 번호 21, 서열 번호 23, 서열 번호 25, 서열 번호 27, 서열 번호 29, 서열 번호 31, 서열 번호 33, 서열 번호 35, 서열 번호 37, 서열 번호 39, 서열 번호 41, 서열 번호 43, 서열 번호 45, 서열 번호 47, 서열 번호 49, 서열 번호 51, 서열 번호 53, 서열 번호 55, 서열 번호 57, 서열 번호 59, 서열 번호 61, 서열 번호 63, 서열 번호 65, 서열 번호 67, 서열 번호 69, 서열 번호 71, 서열 번호 73, 서열 번호 75, 및 서열 번호 77을 포함한다. 선조 유전자-암호화된 코끼리 p53 아미노산 서열의 예는 이에 제한되는 것을 아니지만, 서열 번호 3을 포함한다.
조성물
특정 양태에서, 하나 이상의 코끼리 p53 단백질을 암호화하는 하나 이상의 코끼리 TP53 핵산 서열은 조성물의 형태이다. 따라서, 본 개시내용은 또한 약제학적으로 허용되는 담체 및 (a) 코끼리 p53 단백질을 각각 암호화하는 하나 이상의 핵산 서열 또는 (b) 하나 이상의 코끼리 p53 단백질을 포함하는 조성물을 제공한다. 임의의 적합한 약제학적으로 허용되는 담체는 본 개시내용의 맥락에서 사용될 수 있고, 이러한 담체는 당해 기술 분야에 잘 공지되어 있다. 담체의 선택은, 부분적으로, 조성물이 투여되는 특정 부위, 및 조성물을 투여하는데 사용하는 특정 방법에 의해 결정될 것이다. 조성물을 위한 예시적인 제형은, 이에 제한되는 것을 아니지만, 경구, 주사가능, 그리고 에어로졸 제형을 포함한다.
경구 투여를 위해 적합한 제형은 (a) 액체 용액, 예를 들면, 희석제, 예를 들면, 물, 염수, 또는 음료에 용해되는 하나 이상의 핵산 서열 또는 단백질의 유효량, (b) 하나 이상의 핵산 서열 또는 단백질의 미리 결정된 양을, 고형 또는 과립 형태로 각각 포함하는, 캡슐, 샤쉐, 또는 정제, (c) 적합한 액체 중 현탁액, 및 (d) 적합한 에멀젼을 포함할 수 있다. 정제 형태는 락토스, 만니톨, 옥수수 전분, 감자 전분, 미세결정성 셀룰로스, 아카시아, 젤라틴, 콜로이드성 이산화규소, 크로스카멜로스 나트륨, 탈크, 마그네슘 스테아레이트, 스테아르산, 및 다른 부형제, 착색제, 희석제, 완충제, 습윤제, 보존제, 향미제, 및 약리학적으로 적합한 부형제 중 하나 이상을 포함할 수 있다. 로젠지 형태는 하나 이상의 핵산 서열 또는 단백질을 향미료, 보통 수크로스 및 아카시아 또는 트라가칸트 중에 포함할 수 있고, 뿐만 아니라 파스틸은 활성 성분을 불활성 기재, 예를 들면, 젤라틴 및 글리세린, 또는 수크로스 및 아카시아 중에 포함하고, 에멀젼, 겔 등은 하나 이상의 핵산 서열 또는 단백질 이외에, 당해 기술 분야에 공지된 이러한 부형제를 포함한다.
비경구 투여를 위해 적합한 제형은 항산화제, 완충제, 정균제, 및 제형이 의도하는 수령자의 혈액과 등장성이 되게 하는 용질을 포함할 수 있는 수성 및 비-수성, 등장성 멸균 주사 용액, 및 현탁제, 가용화제, 증점제, 안정화제, 및 보존제를 포함할 수 있는 수성 및 비-수성 멸균 현탁액을 포함한다. 제형은 단위-용량(unit-dose) 또는 다중-용량 밀봉된 용기, 예를 들면, 앰풀 및 바이알로 존재할 수 있고, 주사를 위해 사용 직전에 멸균 액체 부형제, 예를 들면, 물의 첨가만 필요한 냉동-건조(동결건조) 상태로 보관될 수 있다. 임시 주사 용액 및 현탁액은 이전에 기술된 종류의 멸균 분제, 입제, 및 정제로부터 제조될 수 있다.
하나 이상의 핵산 서열 또는 단백질을, 단독으로 또는 다른 적합한 성분과 조합하여 포함하는 에어로졸 투여를 위해 적합한 제형은 흡입을 통해 투여되는 에어로졸 제형 내로 제조될 수 있다. 이들 에어로졸 제형은 압축된 허용되는 추진체, 예를 들면, 디클로로디플루오로메탄, 프로판, 질소 등 내로 위치될 수 있다. 이들은 또한 비-압축된 제제를 위한 약제로서, 예를 들면, 네뷸라이저(nebulizer) 또는 애터마이저(atomizer)로서 제형화될 수 있다.
국소 투여를 위해 적합한 제형은 크림, 로션, 겔, 연고 등을 포함할 수 있다. 다른 적합한 제형이 가능하고, 예를 들면, 좌제는 다양한 기제(bases), 예를 들면, 유화 기제 또는 물-가용성 기제를 사용하여 제조할 수 있다. 질 투여를 위해 적합한 제형은 하나 이상의 핵산 서열 또는 단백질 이외에, 당해 기술 분야에 적합한 것으로 공지된 이러한 담체를 포함하는 페서리, 탐폰, 크림, 겔, 페이스트, 폼, 또는 스프레이 제형으로 존재할 수 있다.
하나의 양태에서, 조성물의 적합한 제형은 단백질의 열 안정성과 동일하거나 낮은 상 전이 온도를 포함할 수 있다. 예를 들면, 25℃의 열 안정성을 갖는 단백질은 23℃의 융점을 포함하는 인지질로 제형화될 수 있다(예를 들면, 1,2-디미리스토일-sn-글리세로-3-포스포콜린(DMPC)). 적합한 인지질은 당해 기술 분야에 잘 공지되어 있다.
상기한 방법의 하나의 측면에서, 조성물은 리포솜을 포함한다. 본원에 사용된 용어 "리포솜"은 지질 이중층으로 구성된 인공적으로 제조된 소포를 언급한다. 본원에 사용된 용어 "지질 이중층"은 지질 분자의 2층으로 이루어진 막을 언급한다. 지질 이중층은 이중층, 예를 들면, 세포 막, 핵 막, 및 바이러스 외피에 천연으로 존재하는 것과 유사한 두께를 가질 수 있다. 예를 들면, 지질 이중층은 약 10 nm 이하의 두께, 예를 들면, 약 1 nm 내지 약 9 nm, 약 2 nm 내지 약 8 nm, 약 2 nm 내지 약 6 nm, 약 2 nm 내지 약 4 nm, 또는 약 2.5 nm 내지 약 3.5 nm의 범위를 가질 수 있다. 지질 이중층은 핵산, 단백질, 이온, 및 다른 분자를 보유하는 장벽이고, 동시에 또한 이들이 목적하지 않는 영역 내로 확산하는 것을 방지한다.
지질 이중층을 형성하는 "지질 분자"는 친수성 헤드 및 소수성 테일을 포함하는 분자를 포함할 수 있다. 지질 분자는 약 14 내지 약 50개의 탄소 원자를 포함할 수 있다. 지질 이중층을 형성할 수 있는 지질 분자의 예는 인지질, 폴리에틸렌 글리콜(PEG)에 접합된 지질, 콜레스테롤, 또는 이의 조합을 포함한다. 리포솜은 단층 소포 또는 다층 소포로서 분류될 수 있다. 본원에 정의된 단층 소포는 챔버 내부에 수성 용액을 포함하는, 양친매성(amphiphilic) 지질 또는 이러한 지질의 혼합물의 단일 이중층이다. 다층 소포는 다수의 동심원 양친매성 지질 이중층으로 이루어진다.
상기 방법의 또다른 측면에서, 리포솜은 미셀, 바이셀, 또는 지질 나노디스크일 수 있다. 본원에 사용된 "미셀"은 소수성 내부를 포함하는 계면활성제 분자의 응집체를 언급한다. 일부 양태에서, 미셀은 리포솜의 친수성 내부 공간 내에 포함될 수 있다. "바이셀"은 디스크-형 미셀이다. 미셀 또는 바이셀은 소수성 핵산, 단백질, 이온, 또는 다른 분자를 포함할 수 있다. 본원에 사용된 용어 "나노디스크(nanodisc)"는 적어도 하나의 인지질 이중층을 언급하고, 여기서, 소수성 가장자리는 적어도 하나의 양친매성(amphipathic) 단백질로 안정화된다.
일부 양태에서, 하나 이상의 핵산 서열 또는 하나 이상의 코끼리 p53 아미노산 서열은 리포솜 내에 캡슐화된다.
또다른 양태에서, 하나 이상의 핵산 서열 또는 하나 이상의 코끼리 p53 단백질은 나노입자 내에 캡슐화될 수 있다. 본원에 정의된 "나노입자"는 100 nm 미만인 적어도 하나의 차원을 갖는 3차원 입자이다. 본 개시내용의 문맥에서, 나노입자는 소수성 코어 및 코어를 둘러싼 친수성 층을 포함할 수 있다. 나노입자는 또한 하나 이상의 모이어티로 데코레이팅된(decorated) 외부 표면을 포함할 수 있다. 본원에 사용된 "모이어티(moiety)"는 분자의 부분 또는 기능적 그룹이다. 하나 이상의 모이어티는 나노입자 코어에 매립되거나, 코어 내에 포함되거나, 적어도 일부의 코어를 형성하는 분자에 부착되거나, 코어에 부착된 분자에 부착되거나, 직접적으로 코어에 부착될 수 있다. 모이어티는 나노입자의 망상내피계와의 상호작용을 감소시키기 위해 선택할 수 있다. 이러한 모이어티는, 예를 들면, 폴리에틸렌 글리콜(PEG)을 포함한다.
하나의 양태에서, 하나 이상의 모이어티는 표적화 모이어티를 포함할 수 있다. 본원에 사용된 "표적화 모이어티"는 특정 세포 유형, 예를 들면, 암 세포에 대한 나노입자를 지시한다. 표적화 모이어티는 바람직하게는 코어로부터 외부로 확장되어 세포 성분과 상호작용을 위해 이용가능하거나 나노입자의 표면 특성에 영향을 준다. 하나의 양태에서, 표적화 모이어티는 코어 또는 코어와 상호작용하는 성분에 테더링(tether)될 수 있다. 표적화 모이어티는 나노입자의 대사 흡수를 수행하기 위한 소분자 운반체, 예를 들면, 콜레스테롤, 당, 또는 인슐린을 포함할 수 있다. 표적화 모이어티는 추가로 분자에 특이적인 항체 또는 리간드, 예를 들면, 표적화된 세포의 외부 상 수용체를 포함할 수 있다. 하나 이상의 표적화 모이어티는 나노입자를 특이적 세포 세포소기관에 대해 표적화할 수 있고, 이에 따라, 나노입자는 특이적 세포 세포소기관에서, 다른 세포소기관 또는 세포질에 비해, 실질적으로 유사한 비-표적화된 나노입자 보다 더 높은 농도로 축적된다. 실질적으로 유사한 비-표적화된 나노입자는 동일한 성분을 표적화된 나노입자와 실질적으로 동일한 상대적 농도(예를 들면, 약 5% 이내)로 포함하지만, 표적화 모이어티가 결핍된다. 나노입자에 의해 표적화될 수 있는 세포 세포소기관은, 예를 들면, 세포 막, 핵, 핵소체, 미토콘드리아, 골지 기관, 골지 소포, 조면 세포질 세망, 평활 세포질 세망, 리소좀, 과산화소체, 세포질, 시토졸, 공포, 및 분비 소포를 포함한다.
또다른 양태에서, 표적화 모이어티, 예를 들면, 표적화 펩타이드, 콜레스테롤, 당, 또는 폴리에틸렌 글리콜은, 특이적 세포 유형의 표적화를 수행하기 위해, 및/또는 단백질의 반감기를 증가시키기 위해, 코끼리 p53 단백질의 변종에 접합될 수 있다.
나노입자는 또한 하나 이상의 치료제(예를 들면, 본원에 기재된 코끼리 TP53-암호화 핵산 또는 p53 단백질)를 포함할 수 있다. 하나의 양태에서, 치료제는 코끼리 p53 단백질의 짧은 펩타이드 세그먼트, 예를 들면, 펩타이드 13-mer 길이를 포함할 수 있다. 치료제는 특이적 세포 유형 내로 방출되고 나노입자의 세포 흡수로 이어질 수 있고, 예를 들면, 나노입자는 특이적 세포 유형과 융합될 수 있다. 또다른 양태에서, 치료제는 특이적 세포 유형의 외부로 방출될 수 있고, 세포 기전, 예를 들면, 거대 음작용에 의해 흡수될 수 있다. 치료제는 나노입자 코어 내에 포함되고, 코어로부터 목적하는 속도로 방출될 수 있다. 일부 양태에서, 코어는 코어가 분해되거나 침식됨에 따라 하나 이상의 치료제를 방출하도록 생분해가능할 수 있다.
조성물은 암을 저해하거나 본원에 기재된 코끼리 p53 핵산 및 단백질의 활성을 향상시키는 하나 이상의 추가 제제 또는 첨가제를 추가로 포함할 수 있다. 상기 제제는 임의로 치료제의 효능을 개선시킬 수 있고, 및/또는 치료제의 불활성화, 변성, 또는 분해를 예방할 수 있다. 예를 들면, 조성물은 소분자 화학요법제, 단클론성 항체, 또는 영상화제(예를 들면, 조영제, 당, 철 착물, 또는 가돌리늄(Gd))를 추가로 포함할 수 있다.
상기한 조성물, 하나 이상의 코끼리 p53-암호화 핵산 서열, 또는 하나 이상의 코끼리 p53 단백질은 키트, 즉, 진단 검정 또는 치료 방법을 수행하기 위해 지시서(instructions)와 함께 미리 결정된 양의 시약의 패키징 조합으로 제공될 수 있다. 키트는 첨가제, 예를 들면, 안정화제, 완충제 등, 뿐만 아니라 키트 사용을 위한 지시서를 포함할 수 있다. 다양한 시약의 상대적 양은 검정의 감수성을 실질적으로 최적화하는 시약의 용액 중 농도로 제공하기 위해 가변적일 수 있다.
암의 저해 방법
본 개시내용은 본원에 기재된 코끼리 p53 단백질을 각각 암호화하는 하나 이상의 핵산 서열, 및 본원에 기재된 하나 이상의 코끼리 p53 단백질, 또는 본원에 기재된 하나 이상의 코끼리 핵산 서열 단백질을 포함하는 조성물을 사용하는 암의 저해 방법을 제공한다. 본원에 사용된 용어 "암을 저해함"은 하나 이상의 암 세포의 성장, 증식 및/또는 전이를 예방, 억제, 차단, 또는 서행을 언급한다. 일부 양태에서, 예를 들면, 본원에 기술된 방법은 사람에서 암이 치료되도록 암 세포 증식의 저해, 암 세포 혈관신생의 저해, 암 세포의 박멸, 및/또는 적어도 하나의 암성 종양의 크기 감소를 촉진할 수 있다.
본원에 기술된 방법은 당해 기술 분야에 공지된 임의의 암 세포 유형, 예를 들면, 방광 암, 골 암, 뇌 암, 유방 암, 자궁경부 암, 결장 암, 식도 암, 담낭 암, 두경부 암(예를 들면, 구강, 인두, 후두, 침샘, 및 부비동 및 비강의 암), 백혈병, 간 암, 폐 암, 림프종, 흑색종, 난소 암, 췌장 암, 전립선 암, 직장 암, 신장 세포 암종, 위(stomach(gastric)) 암, 소장 암, 및 갑상선 암의 성장, 증식, 및/또는 전이를 저해하는데 사용될 수 있다. 암 세포는 본원에 정의된 대상자로부터 유래할 수 있고, 이는 바람직하게는 포유동물이고, 바람직하게는 사람(예를 들면, 암을 갖는 사람)이다. 암 세포는 또한 비-사람 동물, 예를 들면, 모든 포유류 및 비-포유류 척추동물(예를 들면, 이에 제한되는 것은 아니지만, 비-사람 영장류, 양, 개, 고양이, 개, 소, 돼지, 말, 설치류, 가금류, 양서류, 및 파충류)로부터 유래할 수 있다.
일부 양태에서, 암 세포는 암 세포의 집단, 예를 들면, 원발성 암 또는 종양, 전이 암 또는 종양, 또는 암 종양 재생일 수 있다. 하나의 양태에서, 암 세포 또는 암 세포의 집단은 결손(예를 들면, 돌연변이) TP53 유전자 또는 단백질, 예를 들면, TP53 유전자의 결실, 점돌연변이, 삽입, 치환, 또는 유전 재배열을 포함하는 TP53 유전자를 포함하고, 이는 변형된 TP53 발현(예를 들면, 과-발현 또는 불충분(under)-발현), 비정상 기능을 갖는 p53 단백질의 발현, 또는 p53 단백질 발현의 폐지를 전적으로 야기한다. 결손 유전자 또는 결실된 유전자는 하나의 대립유전자(이형접합 변경됨), 또는 2개의 대립유전자(동형접합 변경됨)로 존재할 수 있다. 암 세포 또는 암 세포의 집단은 암 세포 게놈에 걸쳐 다른 게놈 변경을 갖는 정상 TP53 유전자 또는 단백질을 포함할 수 있다.
본원에 기술된 방법에 따라서, 암 세포는 생체외, 생체내, 또는 시험관내에 존재할 수 있다. "생체외"는 세포 또는 조직 내에서 또는 상에서 인공적 환경에서 자연 상태의 최소의 변경을 갖는 유기체 밖에서 수행되는 방법을 언급한다. 대조적으로, 용어 "생체내"는 살아있는 유기체 내에 정상, 비손상 상태에서 수행되는 방법을 언급하는 반면, "시험관내" 방법은 통상의 생물학적 정황으로부터 단리된 유기체의 성분을 사용하여 수행된다.
상기 방법이 시험관내 또는 생체외에서 수행되는 양태에서, 암 세포는 종양 또는 암 세포주일 수 있다. 종양 및 암 세포주는 상업적으로 또는 공개적 공급원(public sources)로부터 입수할 수 있다. 종양 또는 암 세포주를 구입할 수 있는 상업적으로 또는 공개적으로 이용가능한 공급원의 예는, 이에 제한되는 것을 아니지만, 다음을 포함한다: the American Type Culture Collection (ATCC), Manassus, Va.; Deutsche Sammlung von Mikroorganismen and Zellkulturen GmbH (DSMZ) Braunschweig, Germany; Cell Line Service (CLS), Germany; and European Collection of Cell Cultures (ECACC), Salisbury, Great Britain.
다른 양태에서, 본원에 기술된 방법은 생체내 수행되고, 즉, 하나 이상의 코끼리 TP53-암호화 핵산 서열, 하나 이상의 코끼리 p53 단백질, 또는 이의 조성물은 이를 필요로 하는 동물, 바람직하게는 포유동물(예를 들면, 본원에 기재된 것들), 및 바람직하게는 암을 앓고 있는 사람에게 직접적으로 투여된다. 본원에 기술된 방법은 포유동물, 예를 들면, 사람, 개 등에게 생체내 투여를 위해 양호하게 적합하다. 하나 이상의 코끼리 핵산 서열, 단백질, 또는 조성물은 경구, 정맥내, 복강내, 피하, 폐, 경피, 근육내, 비내, 협측, 설하, 또는 좌약 투여를 포함하는 표준 투여 기술을 사용하여 포유동물(예를 들면, 사람, 개 등)에게 투여될 수 있다. 조성물은 바람직하게는 비경구 투여를 위해 적합하다. 본원에 사용된 용어 "비경구"는 정맥내, 근육내, 피하, 직장, 질, 및 복강내 투여를 포함한다. 보다 바람직하게는, 조성물은 포유동물에게 정맥내, 복강내, 또는 피하 주사로 말초 전신 전달을 사용하여 투여된다. 특정 양태에서, 본원에 기재된 하나 이상의 코끼리 핵산 서열, 단백질, 또는 조성물의 암 세포로의 전달 효과는 치료적이고, 즉, 상기 효과는 부분적으로 또는 완전히 질환 및/또는 질환(예를 들면, 암)이 원인인 유해 증상을 치유한다. 이를 위하여, 본원에 기술된 방법은 본원에 기재된 하나 이상의 코끼리 핵산 서열, 단백질, 또는 조성물의 "치료적 유효량"을 투여함을 포함한다. "치료적 유효량"은 목적하는 치료 결과를 성취하기 위해 필요한 용량으로 그리고 필요한 기간 동안 효과적인 양을 언급한다. 치료적 유효량은 인자, 예를 들면, 개체의 질환 상태, 연령, 성별, 및 체중, 및 개체에서 목적하는 반응을 유도하는 하나 이상의 코끼리 핵산 서열, 단백질, 또는 조성물의 능력에 따라서 가변적일 수 있다. 예를 들면, 코끼리 TP53 핵산 또는 단백질의 치료적 유효량은 사람에서 p53 단백질 생물활성을 증가시키고 및/또는 암에 대항하는 p53 신호전달 경로를 향상시키는 양일 수 있다. 바람직하게는, 치료 효과는 암 세포의 사멸을 야기한다.
대안적으로, 약리학적 및/또는 생리적 효과는 예방적일 수 있고, 즉, 상기 효과는 완전히 또는 부분적으로 질환 또는 이의 증상(예를 들면, 암)을 예방한다. 이러한 측면에서, 본원에 기술된 방법은 본원에 기재된 하나 이상의 코끼리 핵산 서열, 단백질, 또는 조성물의 "예방적 유효량"을 투여함을 포함한다. "예방적 유효량"은 목적하는 예방적 결과(예를 들면, 질환 개시의 예방)를 성취하기 위해 필요한 용량으로 그리고 필요한 기간 동안 효과적인 양을 언급한다. 바람직하게는, 예방은 암의 예방을 야기한다.
실시예
다음 실시예는 추가로 본 발명을 예시하지만, 물론, 이의 범위를 제한하는 임의의 방법으로 간주되어서는 안된다.
실시예 1
이러한 실시예는 체질량(body mass)이 암 발생정도와 상호관련되는지를 측정하기 위한 상이한 포유동물 종(코끼리를 포함함)에서 암 비율을 기술한다.
부검 데이터를 동물원 동물로부터 시험하여 암 발생정도가 신체 크기 또는 수명에 따라 증가하는지를 결정하였다. 샌 디에고 동물원(San Diego Zoo)이 수집한 14년간의 부검 데이터[참조: Feng et al., PNAS; 104(42): 16633-16638 (2007)]를 컴파일하고, 종양 발생정도를 36 포유류 종에 대해 계산하고, 크기 및 수명의 6개 규모 순서(orders of magnitude)까지 포괄한다(spanning)[참조: American Cancer Society; Cancer Facts & Figures (2015)]. 코끼리 백과사전으로부터의 데이터[참조: Griner et al., Pathology of Zoo Animals; Zoological Society of San Diego (1983)]를 사용하여 사로잡힌 아프리카(Loxodonta africana) 및 아시아(Elephas maximus) 코끼리에 대한 사망의 원인을 분석하고, 연령 발생정도 및 전체 일생 암 위험을 평가하였다. 이전에 확립된 암 전환 모델[참조: de Magalhaes et al., J Evol Biol; 22(8): 1770-1774 (2009)]을 사용하여, 세포 돌연변이 비율의 감소 퍼센트를 계산하여 100× 암 발병이 없는 세포 덩이(cell mass)의 증가(코끼리 및 사람 간의 차이)를 해명하였다.
분석된 36 포유류 종은 줄무늬풀밭쥐(51 g의 중량, 4.5년의 최대 수명)로부터 코끼리(4800 kg의 중량, 65년의 최대 수명)까지의 범위였다. 암 위험은 분석된 36 종 중에서 포유류 신체 크기 및 최대 수명에 따라 증가하지 않았다(예를 들면, 바위너구리에 대해, 1% [95% CI, 0%-5%]; 아프리카 들개, 8% [95% CI, 0%-16%]; 및 사자, 2% [95% CI, 0%-7%]) (도 1). 어떠한 상당한 상관관계도 질량, 수명, 및 기초 대사율 및 암 발생정도의 어떠한 조합으로도 발견되지 않았다. 코끼리 백과사전 데이터베이스로부터의 644건의 주석이 달린 코끼리 사망 중에서, 일생 암 발생정도는 3.11%인 것으로 밝혀졌다(95% CI, 1.74%-4.47%)(표 1). 더 높은 보존적 평가를 입수하기 위해, 추론된 암 발생정도를 사망의 원인에 대해 적합한 세부사항이 부족한 케이스에 대해 계산하였고, 4.81%의 평가된 코끼리 암 사망율을 도출하였다(95% CI, 3.14%-6.49%). 발암의 대수적 모델을 기초로 하여[참조: de Magalhaes et al., J Evol Biol; 22(8): 1770-1774 (2009)], 돌연변이 비율의 2.17-배 감소는 이의 100× 사람과 비교하여 증가된 세포 덩이를 고려하였을 때 암 발병으로부터 코끼리를 보호하는데 충분한 것으로 계산되었다. 전체적으로, 코끼리의 암 사망율은, 11% 내지 25%의 사람에 대한 암 사망율과 비교하여, 5% 미만인 것으로 밝혀졌다(25).
이러한 실시예의 결과는 코끼리를 포함하는 더 긴 수명을 갖는 더 큰 동물에서, 더 작은 동물과 비교하여, 암이 덜 발병될 수 있다는 것을 입증하였다.
실시예 2
이러한 실시예는 코끼리에서 암-관련된 유전자의 게놈 분석을 기술한다.
게놈 서열 분석을 Ensembl 데이터베이스(release 72) 및 NCBI 진뱅크(GenBank) 데이타베이스에서 아프리카 코끼리 게놈의 공개적으로 이용가능한 스캐폴드에서 수행하고; 특히, 암-관련된 유전자(종양유전자 및 종양 억제제를 포함함)를 시험하였다. TP53의 서열 얼라인먼트를 관련된 종에서 탐구하고, 아프리카 및 아시아 코끼리 TP53 레트로유전자를 클로닝하고 다시 서열분석하였다. 모세관 서열분석을 코끼리 사이의 단일-뉴클레오티드 다형태(SNPs)의 문제를 피하기 위해 단일 코끼리에서 수행하였다. 모든 게놈 서열분석(ILLUMINA® HISEQ 2500® Sequencing System; Illumina Inc., San Diego, CA)을 아프리카 코끼리로부터의 새롭게 추출된 DNA에서 40× 평균 서열 범위(coverage)로 수행하고, 100× TP53 유전자 면적 내의 범위 초과이다.
최대 가능성 계통발생을 사용하여 서열화된 TP53 레트로유전자 클론을 클러스터하고, 아프리카 코끼리 게놈에서 발견된 독특한 유전자의 수를 확인하였다. 계통발생은 코끼리 및 하이랙스에서 서로에 대한 TP53 레트로유전자 유사성의 가시화 뿐만 아니라 선조 TP53 서열에 대한 이들 상관관계를 허용하였다. 이러한 연구로부터 모세관 서열화된 클론은 원형으로 나타내고, 진뱅크로부터 공개된 서열은 사각형으로 나타낸다. 아프리카 코끼리(L. africana) 드래프트 게놈 LoxAfr3은 19 카피의 TP53을 포함한다(도 2). 계통발생학적 분석은 프로세싱된 TP53 카피의 적어도 18개의 개별 클러스터를 나타낸다. 이들 클러스터는 2 그룹인, 표지된 그룹 A 및 그룹 B로 나뉜다. 사람 반수체 게놈은 1 카피의 TP53을 포함하는 반면, Ensembl 및 진뱅크는 아프리카 코끼리 게놈(각각 12 및 20 반수체(haploid) 카피)에서 다수의 TP53 파라로그에 주석이 단다. 코끼리 서열 얼라인먼트는 TP53과 유사한 유전자 구조를 갖는 하나의 TP53 카피가 다른 포유류 종(선조 카피)에서 발견되었음을 나타내었다.
다른 19 카피에는 진짜(true) 인트론이 결핍되고, 이는 이들이 레트로트랜스포지션(retrotransposition)(레트로유전자)으로부터 유래되었음을 제시한다. 심부 범위로 전체-게놈 서열분석은 하나의 선조 카피 및 19 총 레트로유전자 카피를 확인하였고, 이는 TP53에 대해 진뱅크에 주석이 달린 20 총 카피와 유사하였다. 모세관 서열분석으로부터 18 레트로유전자 중 11개는 이전 진-뱅크 주석 및 국소 전체 게놈 서열분석 데이터와 유사하였지만, 동일하지 않았다. 참조 TP53 카피에 걸친 범위의 높은 편차는 아직 성공적으로 어셈블리되지 않을 수 있는 추가의 TP53 코끼리 카피를 나타내었다.
8의 공개된 레트로유전자 카피에 대한 증거는 없고, 아마도 이는 클론의 언더-샘플링(under-sampling), 공개된 게놈에서 미스어셈블리, 또는 각각의 코끼리 사이의 차이 때문이다. 추가의 7 클로닝 서열이 다중 클론으로부터 지지되었지만, 데이터베이스 중 어느 것에서도 발견되지 않았다. 또한 게놈에서 TP53 카피는 폴리머라제 연쇄 반응(PCR) 프라이머에 의해 검출불가능할 수 있을 가능성이 있다. 아시아 코끼리 DNA는 또한 15 내지 20 카피의 그룹 A 및 B TP53 레트로유전자를 포함하는 것으로 밝혀졌다.
코끼리가 TP53 레트로유전자(EP53r)를 발현하는지 여부를 확립하기 위해, TP53 및 이의 레트로유전자의 기능적 분자 분석을 아프리카 및 아시아 코끼리로부터의 말초 혈액 단핵 세포(PBMCs), 및 아프리카 코끼리로부터의 섬유아세포 상에서 수행하였다. RNA를 2 Gy 이온화 방사선에 노출된 PBMC 및 섬유아세포로부터 분리하였고, 역 전사-폴리머라제 연쇄 반응(RT-PCR)을 수행하였다. PCR 프라이머를 설계하여 선조 서열(EP53anc)로부터의 TP53 레트로유전자와 스플라이스 변종를 구분하였다. RT-PCR 생산물을 201bp 및 185bp에서 겔 상에서 관찰하고(도 3A), 그룹 A 및 그룹 B EP53 레트로유전자 각각에 대해 예상된 크기, 및 생어(Sanger) 서열분석은 레트로유전자로서 이의 동일성을 확인하였다. 더 높은 해상도 영상을 도 3B에 나타내었다.
이러한 실시예의 결과는 코끼리가 2개의 그룹(그룹 A 및 그룹 B)으로 나눌 수 있는 19 TP53 레트로유전자(EP53r), 및 하나의 선조 TP53 유전자(EP53anc)를 갖는다는 것을 제시한다.
실시예 3
이러한 실시예는 사람 세포주로 형질감염된 코끼리 EP53 레트로유전자가 단백질로 번역될 수 있는지 여부를 나타낸다.
포유류 발현 벡터를 클로닝하여 myc 단백질로부터 에피토프에 융합된 코끼리 p53 레트로유전자(EP53r) 단백질을 생산하였다. myc 태그를 사용하여 세포 용해물로부터 번역된 단백질을 면역침전시키고/시키거나, 웨스턴 블롯 상 단백질을 조사하였다. 작제물을 5개의 상이한 EP53rs: 레트로유전자 1, 레트로유전자 5, 레트로유전자 7, 레트로유전자 9, 및 레트로유전자 17에 대해 발달시켰다. 이들 레트로유전자를 선택하였는데, 이는 이들이 상이한 EP53 유전자의 스펙트럼을 나타내기 때문이다. 모든 5개의 EP53rs를 전제 크기의 EP53 단백질과 비교하여 절두된(truncated) 단백질로서 발현되었고, 이는 대략 53 kDa이다(사람 p53과 유사함).
사람 배아 신장 세포(HEK293), 마우스 섬유아세포(NIH 3T3), 및 사람 골육종 세포(U-2OS)는 myc-태그된 EP53r 플라스미드(myc-EP53r) 중 하나로 형질감염되었다. HEK293 세포로부터의 데이터를 나타내고, 다른 세포 유형에서 수행된 실험을 대표한다. 지질-기반 형질감염을 수행하고, 세포는 또한 음성 대조군으로서 공(empty) 벡터로 형질감염되었다. 형질감염 후 24시간에, 세포를 항생제를 포함하는 배지에 위치시켜 관심 대상 유전자를 발현하지 않는 세포를 선택적으로 사멸시켰다. 선택이 완료되면, 독시사이클린을 첨가하여 유전자 발현을 유도하고, 이를 웨스턴 블롯으로 확인하였다.
암 세포주 U-2OS(골육종) 및 HCT116(결장 암)을 또한 렌티바이러스 벡터로 감염시켜 코끼리 EP53r 단백질을 발현하는 안정한 세포주를 생산하였다. 렌티바이러스를 제조하기 위해 사용되는 플라스미드는 테트라사이클린-유발성 유전자 발현 플라스미드였고, 여기서, 관심 대상 유전자는 단지 세포가 독시사이클린으로 치료되는 경우 발현된다. 바이러스 형질도입 후 24시간에서, 세포를 항생제를 포함하는 배지에 위치시키고, 관심 대상 유전자를 발현하지 않는 세포를 제거하였다. 선택이 완료되면, 관심 대상 유전자의 발현을 웨스턴 블롯으로 확인하였다.
P53은 DNA 손상에 대한 반응에서 상향조절되어, 형질감염되거나 형질도입된 세포는 관심 대상 유전자를 발현할 수 있고, 세포를 MG132(프로테아제 저해제) 또는 독소루비신(거대분자 생합성을 예방하기 위해 DNA로 삽입됨) 중 어느 하나로 치료하여 DNA 손상을 유도한다는 것을 확인하였다. 테트라사이클린 유발성 세포에 대해, 상기 세포를 MG132 또는 독소루비신으로 치료하기 전에 독시사이클린으로 24 내지 48시간 동안 치료하였다. DNA 손상의 유도 후, 세포를 수거하고 펠릿화하였다. 세포 펠릿을 냉동시키고, 이어서, 포스파타제 및 프로테아제 저해제를 포함하는 세포 용해 완충제에서 용해시켰다. 세포 용해물을 SDS-PAGE 단백질 겔에서 수행하고, 이어서, PVDF 막으로 전달하였다(웨스턴 블롯). 막을 차단하였고, 이어서, 일차 항체로 프로빙하여 p53 단백질 수준을 측정하였다. 블롯을 이차 HRP-컨쥬케이트 항체로 프로빙하고, 단백질 수준을 기질 및 화학발광계(chemiluminometer)를 사용하여 검출하였다. GAPDH를 각 웨스턴 블롯에 대한 적재 대조군으로서 사용하였다. 블롯을 또한 인산화된 EP53r에 대해 세린-15 잔기에서 프로빙하였다(포스포(phospho)-EP53r). DNA 손상은 p53의 인산화를 유도하고, 이는 이러한 단백질과 이의 음성 조절자, 마우스 더블 미뉴트 2(MDM2)와의 상호작용을 감소시킨다[참조: Milczarek et al. Life Sci; 60: 1-11 (1997)].
형질감염된 세포의 10 μM MG132 또는 1 μM 독소루비신로의 치료 후, 단백질 라벨링의 증가를 HEK293 세포에서 모든 5개의 EP53rs에 대해 관찰하였고, 뿐만 아니라 포스포-EP53r에 대한 라벨링의 증가를 관찰하였다(도 4A 및 4B). 이는 유전자의 세포로의 성공적인 전달을 제시하고, EP53r 유전자가 단백질로 번역될 수 있음을 제시한다. 포스포-EP53r의 증가로 MG132가 코끼리 단백질의 프로테아좀 분해를 예방하였음을 확인하였다. 다음에서 EP53rs가 음성 조절자, MDM2와 상호작용할 수 있는지를 결정하였다. EP53rs가 MDM2에 결합할 수 있는지 결정하기 위해, HEK293 세포를 EP53r9로 형질감염시키고, 6 Gy 이온화 방사선을 수행하여 DNA 손상을 유도하였다. 이어서, 발현된 EP53r9 단백질을 항체로 myc 태그에 면역침전시키고, 웨스턴 블롯에서 수행하였다. 면역블롯에서는, 6 Gy 이온화 방사선이 EP53r9 발현 및 인산화를 증가시키고, 이는 DNA 손상시 단백질 안정화를 나타내고, 추가로 MDM2가 myc-EP53r9로 공-면역침전되고, 이는 2개 단백질이 상호작용함을 나타낸다는 것을, 보여준다(도 4C).
이러한 실시예의 결과는 myc-EP53rs가 세포 내로 형질감염되고 DNA 손상에 대한 반응에서 단백질을 생성하고 MDM2와 상호작용할 수 있음을 입증한다.
실시예 4
이러한 실시예는 코끼리 및 사람의 말초 혈액 림프구에서 DNA 손상에 대한 세포 반응을 기술한다.
실험은 다음 3 그룹의 대상자로부터의 말초 혈액 림프구(PBLs)에서 수행한다: 아프리카 및 아시아 코끼리, 유타 유니버시티의 암 유전 연구에 등록된 리-프라우메니 증후군(LFS)을 갖는 환자의 대표적인 임상 코호트, 및 암의 유의한 가족력이 없는 연령-매칭된 사람 대조군(또한 암 유전 연구에 등록됨). LFS를 갖는 환자를 이들의 TP53 돌연변이 상태, 다양한 암 병력, 및 채혈의 가용성을 기초로 하여, 대표적인 샘플로서 포함시키기 위해 선택하였다. 추적조사 실험실 실험은 또한 아프리카 코끼리 섬유아세포, 사람 섬유아세포, 및 HEK293 세포에서 수행하여 결과를 확인하였다.
이온화 방사선(0.5, 2, 5, 6, 10, 및 20 Gy) 또는 독소루비신(0.005-30 μM)을 사용하여 배양된 기본 PBLs에서 DNA 손상을 유도하고, 이어서, 이를 아폽토시스 징후, DNA 복구 효율, 및 세포 주기 저지에 대해 평가하였다. 아폽토시스를 아넥신(Annexin) V(AV) 및 프로피디움 요오다이드(PI)로 염색된 세포의 수를 측정하여 평가하였고; 세포를, 이들이 AV+ PI+인 경우 후기 아폽토시스 상태인 것으로 분류하고, 이들이 AV+ PI-인 경우 조기 아폽토시스 상태인 것으로 분류하였다. 아폽토시스를 또한 APO-TOX GLO™(Promega, Madison, WI) 또는 CASPASE-GLO® 3/7 검정(Promega) 및 CELLTITER-GLO®(Promega)를 사용하여 측정하였다. 결과를, APO-TOX GLO™와 함께 포함된 MULTI-TOX-FLUOR™ 검정(Promega)으로부터의 카운트를 사용하거나, 카스파제 활성이 측정되는 경우 CELLTITER-GLO®를 사용하여, 세포 생존력에 대해 정규화하였다. 아폽토시스의 통계학적으로 유의한 차이가 GRAPHPAD PRISM®에서 계산되었다.
2 Gy 및 6 Gy 이온화 방사선 후, 아프리카 코끼리 PBLs는 사람 PBLs와 비교하여 18시간 후 상당히 상승된 비율의 아폽토시스를 나타내었다(후기 아폽토시스: 각각 14.07%와 비교하여 33.20%; P < .001 (도 5A); 조기 아폽토시스: 각각 11.73%와 비교하여 21.07%; P < .001(도 5B)). 아프리카 코끼리 림프구는 또한 5 μM의 독소루비신에 노출된 경우 18 및 24시간에 후기 아폽토시스(도 6A) 및 조기 아폽토시스(도 6B)의 상당한 증가를 나타내었다.
2 Gy의 이온화 방사선으로 치료된, LFS를 갖는 개체로부터의 말초 혈액 림프구(n = 10), 건강한 대조군(n = 10), 및 1 아프리카 코끼리는, 상이한 수준의 아폽토시스를 나타내었다(아폽토시스는, 치료 없이 배양된 AV+PI+ 세포의 퍼센트에서, 2 Gy 이온화 방사선으로 치료된 AV+PI+ 세포의 퍼센트를 공제하여 계산함). LFS를 갖는 환자의 세포는 건강한 사람 PBLs(7.17%에 대하여 2.71%; P < .001) 및 코끼리 PBLs(14.64%; P < .001)과 비교하여 상당히 더 낮은 아폽토시스를 겪었다(도 7).
림프구와 유사하게, 더 높은 속도의 아폽토시스(증가된 카스파제 3/7 절단의 미터(metric)로서)가 또한 10μM 및 30μM 독소루비신에 의해 DNA 손상이 가해진 코끼리 섬유아세포(도 8)에서 관찰되었다(코끼리: 9.1-배 증가; 사람: 2.24-배 증가; P < .001). 코끼리 섬유아세포 세포는 추가로 0.5 Gy의 이온화 방사선 후 세포 주기 저지와 일치하는 감소된 생존력을 나타내었다(사람: 95.87%와 비교하여 코끼리: 80.81%; P = .01).
P53은 DNA 손상 후 p21 및 MDM2 단백질 유도에서 중요한 역할을 하고[참조: Macleod et al, Genes Dev; 9(8): 935-944 (1995); Yoon et al. PNAS; 99(24): 15632-15637 (2002])], 따라서, p21 발현을 면역블롯으로 평가하여 방사선에 대한 코끼리 세포에서 DNA 손상 반응이 P53에 의존성임을 입증하였다. 코끼리 및 사람 PBLs 둘 다는 이온화 방사선 노출 후 p53 및 p21 단백질 발현의 증가를 나타내었다(도 9). 더 많은 p21 단백질 발현이 사람 PBLs와 비교하여 5시간에 0.5 Gy의 이온화 방사선으로 치료된 코끼리 PBLs에서 관찰되었다(3.5-배 증가에 비해 20.1-배 증가; P = .004). 코끼리 섬유아세포는 또한 사람 섬유아세포의 증가 없음과 비교하여, 5시간에서 2 Gy의 이온화 방사선 후 증가된 p21 단백질 발현을 나타내었다(1.9-배 증가).
사후(post hoc) 분석으로서, 동일한 실험을 PBLs에서 상이한 연령(2, 12, 17, 38, 57, 및 69세)의 다수 아시아 코끼리(n = 6)에서부터 반복하였다. 아시아 코끼리 림프구는 또한 2 Gy의 이온화 방사선에 노출시 아폽토시스의 증가된 비율(사람 세포 23.67%에 비해 50.63%; P < .001)(도 10A) 및 p21 발현의 증가(도 10B)를 입증하였다. 추가로, PBLs에서 아폽토시스 반응은 선형 회귀 및 존크헤르-테르프스트라(Jonckheere-Terpstra) 시험 둘 다로 시험된 경우 아시아 코끼리의 연령에 따라 감소하였고, 이는 비선형 상관관계를 고려한다(도 10C)(2-세 코끼리 18시간에서 2 Gy 방사선을 사용함, 52.53% [95% CI, 35.86%-69.2%] 및 69-세 코끼리, 40.03% [95% CI, 30.64%-49.43%]; P = .002 선형 회귀에 의해; P < .001 존크헤르-테르프스트라 시험에 의해).
HEK293 세포는 p53의 기능을 자연적으로 저해하는 아데노바이러스 단백질을 발현하고; 그러나 마우스 섬유아세포 세포주, NIH3T3은, 기능적 TP53 유전자를 발현한다. 따라서 추가 연구를 NIH3T3 세포에서 수행하여 기능적 야생형 TP53을 또한 발현하는 세포에서 EP53r5 또는 EP53r9 발현의 세포 생존에 미치는 효과를 시험하였다. NIH3T3 세포는 EP53r5 또는 EP53r9로 형질감염되고, 이어서, 독소루비신으로 치료하여 DNA 손상을 유도하였다. 도 11에 나타낸 바와 같이, EP53r5(도 11A) 및 EP53r9(도 11B)로 형질감염된 NIH 3T3 세포의 카스파제 활성의 상당한 증가는 대조군 세포와 비교하여 관찰되고, 이는 EP53r5 및 EP53r9 발현이 기능적 TP53을 이미 발현하는 세포에서 아폽토시스를 증가시킨다는 것을 암시한다.
DNA 복구 효율은 이어서 포스포-히스톤 H2AX(pH2AX) 표지된 초점(foci)의 수, DNA에서 이중-가닥 절단의 지시자를 측정하여 평가하였고, 세포를 2 Gy 이온화 방사선에 의한 DNA 손상 유도 후 1, 5, 10, 18, 24, 및 72시간 동안 배양하였고, 이어서, 평가하였다. 림프구는 DNA 손상에 대한 반응에서 p53-의존성 아폽토시스를 겪었고[참조: Heinrichs et al. Oncogene; 22(4): 555-571 (2003); Lowe et al. Cell; 74(6): 957-967 (1993)], 섬유아세포는 p53-의존성 아폽토시스 및 세포 주기 저지 둘 다를 겪었고[참조: Antoccia et al. J Radiat Res; 50(5): 457-468 (2009); Kastan et al. Cell; 71(4): 587-597 (1992); Attardi et al. Oncogene; 23(4): 973-980 (2004)]; 둘 다의 코끼리 세포 유형을 이에 따라 시험하였다.
이온화 방사선은 사람 및 코끼리 PBLs에서 표지된 pH2AX 초점을 갖는 세포 퍼센트의 상당한 차를 야기하지 않았고, 이는 코끼리에서 증가된 아폽토시스는 더 큰 DNA 손상에 원인이 될 수 없다는 것을 나타낸다(표 2). 세포를 pH2AX 초점(0-5, 6-10, 11-15, 16-20+)의 수로 버리고(binned), 사람 및 코끼리 사이의 DNA 손상 복구 비율에서 상당한 차이가 없음을 나타내었다.
DNA 손상에 대한 반응에서 코끼리 세포에서 유전자 발현의 변화를 확인하기 위해, 코끼리 말초 혈액 림프구를 2 Gy 이온화 방사선으로 치료하였다. 조사되고 비처리된 세포를 37℃에서 5시간 동안 배양하였다. RNA를 세포로부터 추출하고 DNase로 처리하여 게놈 DNA를 제거하였다. RNA-시퀀싱이 수행되고, 방사선에 노출 후 코끼리 세포에서 상위 20 가장 우수하게 상향조절된 유전자가 컴파일되었다. 표 3에서, 회색으로 강조된 유전자는 사람 세포에서 p53의 공지된 표적 또는 조절자이다. 이들 결과는 DNA 손상이 사람 세포에서 DNA 손상에 의해 유도된 p53-신호전달 경로와 유사한 코끼리 세포에서 p53-의존 신호전달 경로를 유도한다는 것을 제시한다.
이러한 실시예의 결과는 코끼리 세포가 DNA 손상에 반응하여 더 높은 수준의 아폽토시스를 실행하고, EP53 단백질이 사람 세포 내로 형질도입되는 경우, 이들 세포는 DNA 손상에 반응하여 더 높은 수준의 아폽토시스를 실행할 수 있다는 것을 증명한다.
실시예 5
이러한 실시예는 EP53 발현이 다양한 EP53 유전자로 형질감염된 사람 암 라인, U-2OS (골육종)의 아폽토시스를 증가시킬 수 있는지 여부를 평가한다.
U-2OS 세포를 EP53r5 또는 EP53 선조(EP53anc)로 형질감염되고, 이어서, 독시사이클린으로 치료하여 EP53r 발현을 유도하였다. 이어서, 세포를 독소루비신으로 치료하여 DNA를 손상시켰다. 도 12A에 나타낸 바와 같이, 카스파제 활성의 상당한 증가는 공 벡터를 갖는 대조군 세포와 비교하여 EP53r5-형질도입된 세포주에서 관찰되었고, 이는 EP53r5 발현이 기능적 TP53을 또한 발현하는 암 세포의 아폽토시스를 증가시킨다고 제시한다.
U-2OS 세포는 또한 EP53anc로 형질도입되었다. 이어서, 이들 세포를 유도하여 EP53anc를 발현하고, 독소루비신으로 치료하여 DNA 손상을 촉발시켰다. 도 12B에 나타낸 바와 같이, EP53anc를 발현시키기 위해 유도된 세포는 공 벡터로 형질도입된 세포와 비교하여 카스파제 활성이 20-배 증가되었다. 이들 세포는 더 많은 인광체(phosphor)-EP53anc를 나타내었고, 이는 p53 표적 유전자, p21 및 MDM2의 증가 때문이다(도 12C). EP53anc를 발현한 세포는 또한 더 낮은 내인성 사람 p53을 발현하였다. 독소루비신 치료의 부재에서 조차도, EP53anc를 발현하는 U-2OS 세포는 공 벡터로 형질도입된 세포와 비교하여 상당한 아폽토시스를 겪었다.
추가 실험이 수행되었고, 여기서, U-2OS 세포는 GFP로 태그된 EP53r9(GFP-EP53r9)로 형질감염되었다. 형질감염-후 24, 48, 또는 72시간 후, 세포를 수거하고, 전체 세포 용해물을 웨스턴 블롯팅을 위해 처리하였다. 블롯은 포스포-EP53r9, 뿐만 아니라 내인성 사람 인광체-p53에 대해 조사하였다. EP53r9의 증가된 발현 이외에, U-2OS 세포는 야생형 p53 반응의 복원을 나타내는 것을 발견하였고, 이는 이들 세포의 아폽토시스를 유도하였다(도 13).
U-2OS 세포는 또한 EP53anc 및 사람 TP53으로 형질감염되고, 독시사이클린으로 유도 후 세포 생존력은 72시간 후 관찰되었다. 코끼리 p53으로 형질감염된 세포에서, 세포 생존력이 35.6%(SEM 1.85)로 떨어지는 반면, 사람 p53으로 형질도입된 세포는 단지 46.1%(SEM 1.12) 세포 생존력으로 떨어지는 것을 발견하였고, 이는 코끼리 p53이 사람 p53 단독 보다 더 많은 사람 암 세포를 사멸할 수 있음을 제시한다. EP53anc로 형질감염된 U-2OS 세포는 또한 사람 p53으로 형질감염된 세포(10.89%, SEM 0.12)와 비교하여 카스파제 활성의 증가(14.22%, SEM 0.23)를 나타내었고, 이는 코끼리 p53 단백질의 유도 후 아폽토시스 활성의 증가와 일치한다.
사람 결장 암 세포의 세포 노화에 미치는 EP53r9 발현의 효과를 조사하기 위해, HCT116 암 세포를 EP53r9를 암호화하는 테트라사이클린-유발성 벡터로 형질도입하였다. 이어서, 단백질 발현을 독시사이클린으로 유도하고, 이어서, 세포를 독소루비신으로 치료하여 DNA를 손상시켰다. HCT116-EP53r9 세포는 대조군 세포와 비교하여 상당히 더 높은 카스파제 활성을 나타내었다(도 14A). 웨스턴 블롯을 수행하여 이들 세포에서 EP53r9의 발현을 확인하였다(도 14B). 증가된 농도의 독시사이클린으로 치료된 세포가 EP53r9를 발현하지 않는 세포와 비교하여 보다 내인성 사람 인산화된-p53(Ser15)을 발현하였음을 발견하였다. 세포를 플래그-태크된 EP53r9로 형질도입하였고, 플래그에 대한 항체는 EP53r9의 발현을 증명하기 위해 사용하였다. 세포를 5-FU로 처리하여 p53 경로를 활성화시켰다. 이들 결과는 EP53r9가 이들 세포에서 활성화된 내인성 p53의 양을 증가시켜 아폽토시스를 증가시켰음을 제시한다.
이러한 실시예의 결과는 암 세포주에서 EP53의 유도가 아폽토시스의 상당한 증가를 야기함을 입증한다.
본원에 인용된 공보, 특허 출원, 및 특허를 포함하는 모든 참조 문헌은, 참조 문헌이 개별적으로 및 구체적으로 참조로서 포함되는 것을 나타내고 본원에 이의 전문이 기술되는 것 같이 이와 동일한 범위까지 참조로써 본원에 포함된다.
본 발명을 기술하는 문맥 내에서 (특히 하기 청구범위의 문맥 내에서) 용어 하나("a" 및 "an") 및 "상기(the)" 및 "적어도 하나(at least one)" 및 유사한 지시대상의 사용은 본원에 달리 지시되지 않거나 문맥에 의해 명확하게 부인되지 않는 한, 단수 및 복수 둘 다를 포함하는 것으로 이해된다. 하나 이상의 항목(예를 들면, "A 및 B 중 적어도 하나")의 목록이 뒤따르는 용어 "적어도 하나"의 사용은 본원에 달리 지시되지 않거나 문맥에 의해 명확하게 부인되지 않는 한, 열거된 항목으로부터 선택된 하나의 항목(A 또는 B) 또는 열거된 항목 중 2개 이상의 임의의 조합(A 및 B)을 의미하는 것으로 이해되어야 한다. 용어 "포함하는(comprising)", "갖는(having)", "포함하는(including)" 및 "함유하는(containing)"은, 달리 나타내지 않는 한, 개방형 용어(즉, "이에 제한되는 것은 아니지만, 포함함"을 의미함)로서 이해되어야 한다. 본원에 기재된 값의 범위의 열거는, 달리 지시하지 않는 한, 단지 개별적으로 범위 내에 속하는 각각의 개별적인 값을 언급하는 약칭 방법의 역할을 하는 것을 의도하고, 각각의 개별적인 값은 개별적으로 본원에 인용된 것과 같이 명세서 내에 포함된다. 본원에 기재된 모든 방법은 본원에 달리 지시되지 않거나 문맥에 의해 명확하게 부인되지 않는 한, 임의의 적합한 순서로 수행될 수 있다. 본원에 제공된 임의의 그리고 모든 예, 또는 예시적인 표현(예를 들면, "와 같은(such as)")의 사용은 단지 본 발명을 더 분명히 하기 위한 의도이고, 달리 주장되지 않는 한 본 발명의 범위를 제한하지 않는다. 명세서에 기재된 어떠한 표현도 본 발명의 실시에 필수적인 임의의 주장되지 않은 요소를 지시하는 것으로 이해하여서는 안 된다.
본 발명의 바람직한 양태는 본 발명을 수행하기 위해 본 발명자들에게 공지된 가장 최선의 방식을 포함하여 본원에 기술된다. 이러한 바람직한 양태의 변형은 상기 기술을 읽으면 당해 기술 분야의 일반적인 숙련가에게 명백할 것이다. 본 발명자들은 당해 기술 분야의 숙련가가 이러한 변형을 적합하게 사용할 것이라고 예상하고, 본 발명자들은 본 발명이 특히 본원에 기술된 것 이외에 다르게 실시되는 것을 의도한다. 따라서, 본 발명은 적용가능한 법에 의해 허용되는 첨부된 청구범위에 인용된 주제의 모든 변형 및 등가물을 포함한다. 또한, 모든 가능한 이의 변형에서 상기한 요소의 임의의 조합은 본원에 달리 나타내지 않는 한 그리고 문맥에서 달리 명백하게 부정하지 않는 한, 본 발명에 포함된다.
SEQUENCE LISTING
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TECHNION RESEARCH & DEVELOPMENT FOUNDATION LIMITED
<120> METHODS AND COMPOSITIONS FOR PREVENTING OR TREATING CANCER
<130> 026389-9173-WO00
<150> US 62/239,103
<151> 2015-10-08
<150> US 62/379,179
<151> 2016-08-24
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actaagcgag cactgcccac caacaccagc tcctctaccc agccaaagaa gaagccactg 960
gatgaagaat atttcaccct tcagatccgt gggcgtgaac gcttcaagat gttcctagag 1020
ctaaatgagg ccttggagct gaaggatgcc caggctggga aggagccaga ggggagccgg 1080
gctcactcca gcccttcgaa gtctaagaag ggacagtcta cctcccgcca taaaaaacca 1140
atgttcaaga gagagggacc tgactcagac tga 1173
<210> 3
<211> 390
<212> PRT
<213> Loxodonta africana
<400> 3
Met Glu Glu Pro Gln Ser Asp Leu Ser Thr Glu Leu Pro Leu Ser Gln
1 5 10 15
Glu Thr Phe Ser Tyr Leu Trp Glu Leu Leu Pro Glu Asn Pro Val Leu
20 25 30
Ser Pro Thr Leu Pro Pro Ala Val Glu Val Met Asp Asp Leu Leu Leu
35 40 45
Ser Glu Asp Thr Ala Asn Trp Leu Glu Ser Gln Val Glu Ala Gln Gly
50 55 60
Met Ser Thr Thr Pro Ala Pro Ala Thr Pro Thr Pro Val Ala Pro Ala
65 70 75 80
Pro Ala Thr Ser Trp Thr Leu Ser Ser Ser Val Pro Ser Gln Lys Thr
85 90 95
Tyr Pro Gly Thr Tyr Gly Phe Arg Leu Gly Phe Leu His Ser Gly Thr
100 105 110
Ala Lys Ser Val Thr Cys Thr Tyr Ser Pro Asp Leu Asn Lys Leu Phe
115 120 125
Cys Gln Leu Ala Lys Thr Cys Pro Val Gln Leu Trp Val Ala Ser Pro
130 135 140
Pro Pro Pro Gly Thr Arg Val Arg Thr Met Ala Ile Tyr Lys Lys Ser
145 150 155 160
Glu His Met Thr Glu Val Val Lys Arg Cys Pro His His Glu Arg Cys
165 170 175
Ser Asp Ser Ser Asp Gly Leu Ala Pro Pro Gln His Leu Ile Arg Val
180 185 190
Glu Gly Asn Leu Arg Ala Glu Tyr Leu Glu Asp Ser Ile Thr Leu Arg
195 200 205
His Ser Val Val Val Pro Tyr Glu Pro Pro Glu Val Gly Ser Asp Cys
210 215 220
Thr Thr Ile His Phe Asn Phe Met Cys Asn Ser Ser Cys Met Gly Gly
225 230 235 240
Met Asn Arg Arg Pro Ile Leu Thr Ile Ile Thr Leu Glu Asp Ser Ser
245 250 255
Gly Asn Leu Leu Gly Arg Asn Ser Phe Glu Val Arg Ile Cys Ala Cys
260 265 270
Pro Gly Arg Asp Arg Arg Thr Glu Glu Glu Asn Phe His Lys Lys Gly
275 280 285
Glu Pro Cys Pro Glu Pro Pro Pro Pro Gly Arg Ser Thr Lys Arg Ala
290 295 300
Leu Pro Thr Asn Thr Ser Ser Ser Thr Gln Pro Lys Lys Lys Pro Leu
305 310 315 320
Asp Glu Glu Tyr Phe Thr Leu Gln Ile Arg Gly Arg Glu Arg Phe Lys
325 330 335
Met Phe Leu Glu Leu Asn Glu Ala Leu Glu Leu Lys Asp Ala Gln Ala
340 345 350
Gly Lys Glu Pro Glu Gly Ser Arg Ala His Ser Ser Pro Ser Lys Ser
355 360 365
Lys Lys Gly Gln Ser Thr Ser Arg His Lys Lys Pro Met Phe Lys Arg
370 375 380
Glu Gly Pro Asp Ser Asp
385 390
<210> 4
<211> 1129
<212> DNA
<213> Loxodonta africana
<400> 4
atggaggagc ccgagtcaga tctcagtact gagctccctc tgagtcaaga gacttttttg 60
tacttgggga aactccttcc tgagaagctg gttctgtccc cctcactgtc cccagcagcg 120
gaggcaggag acgatctgct actcccagaa gatgctgcag actggctaga aagccaagct 180
ggggctcaag aaacatcagc agcccctgca ccagccaccc ttataccagc ctcctcctgg 240
acactctcgt cctctgtccc ttcccagaag acctactgca gcaactgtgg tttccgtctt 300
ggcttcctgc attctgggac agccaagtct gtcacctgca tgtactcccc tgaccttaac 360
aagctgtttt gccagctggc aaagacctgt ccagtgcagc cgtagctcag ctcaccaccc 420
caccccagca cctgtgttca caccatggcc atctaccaga cgtcagcata tgacagaggt 480
catgcagcac tgcccccacc ttgagtgctg ctctgactat agcgacggcc tggccgctcc 540
tcagcatctt atccaggtgg gagaaatcct gtgtgctgat atttgtagga caccatcact 600
ctttgacata gtgtggggta ccctatgagc tacctcaggt cggctctgac taccaccatc 660
cacttcaact tcatgtgtag cagctcctgc aaggggggga ggaacccatc ctcaccatca 720
tcacactgga agactccagt ggtaatctgc taggacacaa cagtttcgaa gtgcatattt 780
gtacctgttc tgggagagac agacgtacag aggaagaaaa tttccacaac aagtgggagc 840
caccctctga gaggatcact aagtaagcac tgccaccagc actagctccc ctaccgagcc 900
aaagaagaag ccagtggatg aaaaatattt cacccttcag atccatgggc atgaatgatt 960
caagatattc ctagagttga atgaggcact ggagctgaag gatgcccagg ctgggaagca 1020
gccagagggg agcagggctc aatgcagcct tccaaactct aagaaagggg aatctaccac 1080
ccactgtaaa aaactaatgt tcaagagaga ggggcctgac tcagactga 1129
<210> 5
<211> 361
<212> PRT
<213> Loxodonta africana
<400> 5
Met Glu Glu Pro Glu Ser Asp Leu Ser Thr Glu Leu Pro Leu Ser Gln
1 5 10 15
Glu Thr Phe Leu Tyr Leu Gly Lys Leu Leu Pro Glu Lys Leu Val Leu
20 25 30
Ser Pro Ser Leu Ser Pro Ala Ala Glu Ala Gly Asp Asp Leu Leu Leu
35 40 45
Pro Glu Asp Ala Ala Asp Trp Leu Glu Ser Gln Ala Gly Ala Gln Glu
50 55 60
Thr Ser Ala Ala Pro Ala Pro Ala Thr Leu Ile Pro Ala Ser Ser Trp
65 70 75 80
Thr Leu Ser Ser Ser Val Pro Ser Gln Lys Thr Tyr Cys Ser Asn Cys
85 90 95
Gly Phe Arg Leu Gly Phe Leu His Ser Gly Thr Ala Lys Ser Val Thr
100 105 110
Cys Met Tyr Ser Pro Asp Leu Asn Lys Leu Phe Cys Gln Leu Ala Lys
115 120 125
Thr Cys Pro Val Gln Pro Leu Ser Ser Pro Pro His Pro Ser Thr Cys
130 135 140
Val His Thr Met Ala Ile Tyr Gln Thr Ser Ala Tyr Asp Arg Gly His
145 150 155 160
Ala Ala Leu Pro Pro Pro Val Leu Leu Leu Arg Arg Pro Gly Arg Ser
165 170 175
Ser Ala Ser Tyr Pro Gly Gly Arg Asn Pro Val Cys Tyr Leu Asp Thr
180 185 190
Ile Thr Leu His Ser Val Gly Tyr Pro Met Ser Tyr Leu Arg Ser Ala
195 200 205
Leu Thr Thr Thr Ile His Phe Asn Phe Met Cys Ser Ser Ser Cys Lys
210 215 220
Gly Gly Arg Asn Pro Ser Ser Pro Ser Ser His Trp Lys Thr Pro Val
225 230 235 240
Val Ile Cys Asp Thr Thr Val Ser Lys Cys Ile Phe Val Pro Val Leu
245 250 255
Gly Glu Thr Asp Val Gln Arg Lys Lys Ile Ser Thr Thr Ser Gly Ser
260 265 270
His Pro Leu Arg Gly Ser Leu Ser Lys His Cys His Gln His Leu Pro
275 280 285
Tyr Arg Ala Lys Glu Glu Ala Ser Gly Lys Ile Phe His Pro Ser Asp
290 295 300
Pro Trp Ala Met Ile Gln Asp Ile Pro Arg Val Glu Gly Thr Gly Ala
305 310 315 320
Glu Gly Cys Pro Gly Trp Glu Ala Ala Arg Gly Glu Gln Gly Ser Met
325 330 335
Gln Pro Ser Lys Leu Glu Arg Gly Ile Tyr His Pro Leu Lys Thr Asn
340 345 350
Val Gln Glu Arg Gly Ala Leu Arg Leu
355 360
<210> 6
<211> 1136
<212> DNA
<213> Loxodonta africana
<400> 6
atggaggagc ccgagtcaga tctcagtact gagctccttc tgagtcaaga gactttttcg 60
tacttgggga aactccttcc tgagaagctg gttctgtccc cctcactgtc cccagcagcg 120
gaggcagtag acgatctgct actcccagaa gatgctgcag actggctaga aagccaagct 180
ggggctcaag gaatatcagc agcccctgca ccagccaccc ttacaccagc cacctcctag 240
acactttcat cctctgtccc ttcccagaag acctactgca gcaactgtgg tttccatctt 300
ggcttcctgc attctgggac agccaagtct gtcacctgca cgtactcccc tgaccttaac 360
aagctgttct gccagctggc aaagacctgt ccagtgcagc cgtagctcag ctcaccaccc 420
cactccaccc cagcacctgt gttcacacca tggccatcta ccagatgtca gcacatgaca 480
gaggtcgtgc agcactgccc ccatcttgag tgctactccg actatagcga tggcctggcc 540
gctcctcagc atcttatcca ggtgggagga atcctgcgtg ctgatatttg taggacacca 600
ttactcttcg acatagtgtg gggtacccta tgagctacct caggtcggtt ctgactacca 660
ccatccactt caacttcatg tgtagcagct cctgcatggg gggggggaac ccatcctcac 720
catcatcaca ctggaagact ccgatggtaa tctgctagga cacaacagtt tcgaggtgca 780
tatttgtact gttctgggag agacagacgt acagaggaag aaaattttcc acaacaagtg 840
gggagccagc ctctgagagg atcactgagt aagcactgcc caccagcacc agctcctcta 900
ccgagccaaa gaagaagcca gtggacgaaa aatatttcac ccttaagatc catgggcatg 960
aatgcttcaa gatgttccta gagttgaacg aggcattgga gctgaaggat gcccaggctg 1020
ggaagcagtc agaggggagc agggatcaat gcagccttcc aaactctagg aaaggggaat 1080
ctaccaccca ctgtaaaaaa ctaatgttca agagagaggg gcctgactca gactga 1136
<210> 7
<211> 369
<212> PRT
<213> Loxodonta africana
<400> 7
Met Glu Glu Pro Glu Ser Asp Leu Ser Thr Glu Leu Leu Leu Ser Gln
1 5 10 15
Glu Thr Phe Ser Tyr Leu Gly Lys Leu Leu Pro Glu Lys Leu Val Leu
20 25 30
Ser Pro Ser Leu Ser Pro Ala Ala Glu Ala Val Asp Asp Leu Leu Leu
35 40 45
Pro Glu Asp Ala Ala Asp Trp Leu Glu Ser Gln Ala Gly Ala Gln Gly
50 55 60
Ile Ser Ala Ala Pro Ala Pro Ala Thr Leu Thr Pro Ala Thr Ser Thr
65 70 75 80
Leu Ser Ser Ser Val Pro Ser Gln Lys Thr Tyr Cys Ser Asn Cys Gly
85 90 95
Phe His Leu Gly Phe Leu His Ser Gly Thr Ala Lys Ser Val Thr Cys
100 105 110
Thr Tyr Ser Pro Asp Leu Asn Lys Leu Phe Cys Gln Leu Ala Lys Thr
115 120 125
Cys Pro Val Gln Pro Leu Ser Ser Pro Pro His Ser Thr Pro Ala Pro
130 135 140
Val Phe Thr Pro Trp Pro Ser Thr Arg Cys Gln His Met Thr Glu Val
145 150 155 160
Val Gln His Cys Pro His Leu Glu Cys Tyr Ser Asp Tyr Ser Asp Gly
165 170 175
Leu Ala Ala Pro Gln His Leu Ile Gln Val Gly Gly Ile Leu Arg Ala
180 185 190
Asp Ile Cys Arg Thr Pro Leu Leu Phe Asp Ile Val Trp Gly Thr Leu
195 200 205
Ala Thr Ser Gly Arg Phe Leu Pro Pro Ser Thr Ser Thr Ser Cys Val
210 215 220
Ala Ala Pro Ala Trp Gly Gly Gly Thr His Pro His His His His Thr
225 230 235 240
Gly Arg Leu Arg Trp Ser Ala Arg Thr Gln Gln Phe Arg Gly Ala Tyr
245 250 255
Leu Tyr Cys Ser Gly Arg Asp Arg Arg Thr Glu Glu Glu Asn Phe Pro
260 265 270
Gln Gln Val Gly Ser Gln Pro Leu Arg Gly Ser Leu Ser Lys His Cys
275 280 285
Pro Pro Ala Pro Ala Pro Leu Pro Ser Gln Arg Arg Ser Gln Trp Thr
290 295 300
Lys Asn Ile Ser Pro Leu Arg Ser Met Gly Met Asn Ala Ser Arg Cys
305 310 315 320
Ser Ser Thr Arg His Trp Ser Arg Met Pro Arg Leu Gly Ser Ser Gln
325 330 335
Arg Gly Ala Gly Ile Asn Ala Ala Phe Gln Thr Leu Gly Lys Gly Asn
340 345 350
Leu Pro Pro Thr Val Lys Asn Cys Ser Arg Glu Arg Gly Leu Thr Gln
355 360 365
Thr
<210> 8
<211> 1130
<212> DNA
<213> Loxodonta africana
<400> 8
atggaggagc ctcagtcaga tctcagtact gagctccctc tgagtcaaga gactttttca 60
tgcttgggga aactccttcc tgagaagctg gttctgtccc cctcactgtc cccagcagcg 120
gaggcagtag acgatctgct actcccagaa gatgctgcag actgcctaga aagccaagct 180
ggggctcaag gaatatcagc agcccctgca ccagccaccc ttacaccagc caccgcctgg 240
acactctcat cctctgtccc ttcccagaag acctactgca gcaactgtgg tttccgtctt 300
ggcttcctgc attctgggac agccaagtct gtcacctgca tgtactcccc tggccttaac 360
aagctgtttt gccagctggc aaagacctgt ccagtgcaac cgtagctcag ctcaccaccc 420
caccccagca cctgtgttca caccatggcc atctaccaga tgtcagcata tgacagaggt 480
cgtgcagcac tgcccccacc ttgagtgctg ctccgactat agcgatggcc tggccgctcc 540
tcagcatctt atccaggtgg gaggaatcct gcgtgctgat atttgtagga caccatcact 600
cttcgacata gtgtggggta tcctatgagc tacctcaggt cggttctgac taccaccatc 660
cacttcaact tcatgtgtag cagctcctgc atggggcggg gcgaacccat cctcaccatc 720
atcacactgg aagactccga tggtaatctg ctaggacaca acagtttcga ggtgcatatt 780
tgtactgttc tgggagagac agacgtacag aggaagaaaa tttccacaac aagtgggagc 840
caccctctga gaggatcact aagtaagcac tgcgcaccag caccagctcc tctaccgagc 900
caaagaagaa gccagtggat gaaaaatatt tcacccttaa gatccgtggg catgaatgct 960
tcaagatgtt cctagagttg aatgaggcat tggagctgaa ggatgcccag gctgggaagc 1020
agccagaagg gagcagggct caatgcagcc ttccaaactc taagaaaggg gaatctacca 1080
cccactgtaa aaaactaatg ttcaagagag aggggcctga ctcagactga 1130
<210> 9
<211> 367
<212> PRT
<213> Loxodonta africana
<400> 9
Met Glu Glu Pro Gln Ser Asp Leu Ser Thr Glu Leu Pro Leu Ser Gln
1 5 10 15
Glu Thr Phe Ser Cys Leu Gly Lys Leu Leu Pro Glu Lys Leu Val Leu
20 25 30
Ser Pro Ser Leu Ser Pro Ala Ala Glu Ala Val Asp Asp Leu Leu Leu
35 40 45
Pro Glu Asp Ala Ala Asp Cys Leu Glu Ser Gln Ala Gly Ala Gln Gly
50 55 60
Ile Ser Ala Ala Pro Ala Pro Ala Thr Leu Thr Pro Ala Thr Ala Trp
65 70 75 80
Thr Leu Ser Ser Ser Val Pro Ser Gln Lys Thr Tyr Cys Ser Asn Cys
85 90 95
Gly Phe Arg Leu Gly Phe Leu His Ser Gly Thr Ala Lys Ser Val Thr
100 105 110
Cys Met Tyr Ser Pro Gly Leu Asn Lys Leu Phe Cys Gln Leu Ala Lys
115 120 125
Thr Cys Pro Val Gln Pro Leu Ser Ser Pro Pro His Pro Ser Thr Cys
130 135 140
Val His Thr Met Ala Ile Tyr Gln Met Ser Ala Tyr Asp Arg Gly Arg
145 150 155 160
Ala Ala Leu Pro Pro Pro Val Leu Leu Arg Leu Arg Trp Pro Gly Arg
165 170 175
Ser Ser Ala Ser Tyr Pro Gly Gly Arg Asn Pro Ala Cys Tyr Leu Asp
180 185 190
Thr Ile Thr Leu Arg His Ser Val Gly Tyr Pro Met Ser Tyr Leu Arg
195 200 205
Ser Val Leu Thr Thr Thr Ile His Phe Asn Phe Met Cys Ser Ser Ser
210 215 220
Cys Met Gly Arg Gly Glu Pro Ile Leu Thr Ile Ile Thr Leu Glu Asp
225 230 235 240
Ser Asp Gly Asn Leu Leu Gly His Asn Ser Phe Glu Val His Ile Cys
245 250 255
Thr Val Leu Gly Glu Thr Asp Val Gln Arg Lys Lys Ile Ser Thr Thr
260 265 270
Ser Gly Ser His Pro Leu Arg Gly Ser Leu Ser Lys His Cys Ala Pro
275 280 285
Ala Pro Ala Pro Leu Pro Ser Gln Arg Arg Ser Gln Trp Met Lys Asn
290 295 300
Ile Ser Pro Leu Arg Ser Val Gly Met Asn Ala Ser Arg Cys Ser Ser
305 310 315 320
Met Arg His Trp Ser Arg Met Pro Arg Leu Gly Ser Ser Gln Lys Gly
325 330 335
Ala Gly Leu Asn Ala Ala Phe Gln Thr Leu Arg Lys Gly Asn Leu Pro
340 345 350
Pro Thr Val Lys Asn Cys Ser Arg Glu Arg Gly Leu Thr Gln Thr
355 360 365
<210> 10
<211> 1130
<212> DNA
<213> Loxodonta africana
<400> 10
atggaggagg ctcagtcaga tctcagtact gagctccctc tgagtcaaga gactttttca 60
tgcttgggga aactccttcc tgagaaggtg gttctgtccc cctcactgtc cccagcagcg 120
gaggcagtag acgatctgct actcccagaa gatgctgcag actgcctaga aagccaagct 180
ggggctcaag gaatatcagc agcccctgca ccagccaccc ttacaccagc cacctcctgg 240
acactctcat cctctgtccc ttcccagaag acctactgca gcaactgtgg tttccgtctt 300
ggcttcctgc attctgggac agccaagtct gtcacctgca tgtactcccc tggccttaac 360
aagctgtttt gccagctggc aaagacctgt ccagtgcagc cgtagctcac ctcaccagcc 420
caccccagca cctgtgttca caccatggcc atctaccaga tgtcagcata tgacagaggt 480
cgtgcagcac tgcccccacc ttgagtgctg ctccgactat agcgatggcc tggccgctcc 540
tcagcatctt atccaggtgg gaggaatcct gcgtgctgat atttgtagga caccatcact 600
cttcgacata gtgtggggta tcctatgagc tacctcaggt cggttctgac taccaccatc 660
cacttcaact tcatgtgtag cagctcctgc atggggcggg gggaacccat cctcaccatc 720
atcacactgg aagactccga tggtaatctg ctaggacaca acagtttcga ggtgcatatt 780
tgtactgttc tgggagagac agacgtacag aggaagaaaa tttccacaac aagtgggagc 840
caccctctga gaggatcact aagtaagcac tgcccaccag caccagctcc tctaccgagc 900
caaagaagaa gccagcggat gaaaaatatt tcacccttaa gatccgtggg catgaatgct 960
tcaagatgtt cctagagttg aatgaggcat tggagctgaa ggatgcccag gctgggaagc 1020
agccagaagg gagcagggct cgatgcagcc ttccaaactc taagaaaggg gaatctacca 1080
cccactgtaa aaaactaatg ttcaagagag aggggcctga ctcagactga 1130
<210> 11
<211> 367
<212> PRT
<213> Loxodonta africana
<400> 11
Met Glu Glu Ala Gln Ser Asp Leu Ser Thr Glu Leu Pro Leu Ser Gln
1 5 10 15
Glu Thr Phe Ser Cys Leu Gly Lys Leu Leu Pro Glu Lys Val Val Leu
20 25 30
Ser Pro Ser Leu Ser Pro Ala Ala Glu Ala Val Asp Asp Leu Leu Leu
35 40 45
Pro Glu Asp Ala Ala Asp Cys Leu Glu Ser Gln Ala Gly Ala Gln Gly
50 55 60
Ile Ser Ala Ala Pro Ala Pro Ala Thr Leu Thr Pro Ala Thr Ser Trp
65 70 75 80
Thr Leu Ser Ser Ser Val Pro Ser Gln Lys Thr Tyr Cys Ser Asn Cys
85 90 95
Gly Phe Arg Leu Gly Phe Leu His Ser Gly Thr Ala Lys Ser Val Thr
100 105 110
Cys Met Tyr Ser Pro Gly Leu Asn Lys Leu Phe Cys Gln Leu Ala Lys
115 120 125
Thr Cys Pro Val Gln Pro Leu Thr Ser Pro Ala His Pro Ser Thr Cys
130 135 140
Val His Thr Met Ala Ile Tyr Gln Met Ser Ala Tyr Asp Arg Gly Arg
145 150 155 160
Ala Ala Leu Pro Pro Pro Val Leu Leu Arg Leu Arg Trp Pro Gly Arg
165 170 175
Ser Ser Ala Ser Tyr Pro Gly Gly Arg Asn Pro Ala Cys Tyr Leu Asp
180 185 190
Thr Ile Thr Leu Arg His Ser Val Gly Tyr Pro Met Ser Tyr Leu Arg
195 200 205
Ser Val Leu Thr Thr Thr Ile His Phe Asn Phe Met Cys Ser Ser Ser
210 215 220
Cys Met Gly Arg Gly Glu Pro Ile Leu Thr Ile Ile Thr Leu Glu Asp
225 230 235 240
Ser Asp Gly Asn Leu Leu Gly His Asn Ser Phe Glu Val His Ile Cys
245 250 255
Thr Val Leu Gly Glu Thr Asp Val Gln Arg Lys Lys Ile Ser Thr Thr
260 265 270
Ser Gly Ser His Pro Leu Arg Gly Ser Leu Ser Lys His Cys Pro Pro
275 280 285
Ala Pro Ala Pro Leu Pro Ser Gln Arg Arg Ser Gln Arg Met Lys Asn
290 295 300
Ile Ser Pro Leu Arg Ser Val Gly Met Asn Ala Ser Arg Cys Ser Ser
305 310 315 320
Met Arg His Trp Ser Arg Met Pro Arg Leu Gly Ser Ser Gln Lys Gly
325 330 335
Ala Gly Leu Asp Ala Ala Phe Gln Thr Leu Arg Lys Gly Asn Leu Pro
340 345 350
Pro Thr Val Lys Asn Cys Ser Arg Glu Arg Gly Leu Thr Gln Thr
355 360 365
<210> 12
<211> 1129
<212> DNA
<213> Loxodonta africana
<400> 12
atggaggagc ccaagtcaga tctcagtact gagctccctc tgagtcaaga gactttttca 60
tacttgggga aactccttcc tgagaagctg gttctgtccc cctcactgtc cccagcagcg 120
gaggcagtag acgatctgct gctcccagaa gatgctgcag actgcctaga aagccaagct 180
ggggctcaag aaatatcagc agcccctgca ccagccacac ttacaccagc cacctcctgg 240
acactctcat cctctgtccc ttcccagaag acctactgca gcaactgtgg tttccgtctt 300
ggcttcctgc attctgggac agccaagtct gtcacctgca tgtactcccc tggccttaac 360
aagctgtttt gccagctggc aaagacctgt ccagtgcagc cgtagctcag ctcaccaccc 420
caccccagca cctgtgttca caccatggcc atctaccaga tgtcagcata tgacagaggt 480
cgtgcagcac tgcccccacc ttgagtgctg ctctgactat accgatggcc tggccgctcc 540
tcagcatctt atccaggtgg gaggaatcct gcgtgctgat atttgtagga caccatcact 600
cttcaacata gtgtggggta ccctatgagc tacctcaggt cggttctgac taccaccatc 660
cacttcaact tcatgtgtag caggctcctg catggggggg ggaacccatc ctcaccatca 720
tcacactgga agactccgat ggtaatctgc taggacacaa cagtttcgag gtgcatattt 780
gtactgttct gggagagaca gatgtacaga ggaagaaaat ttccacaaca agtgggagcc 840
accctctgag aggatcacta agtaagcact gcacaccagc accagctcct ctactgagcc 900
aaagaagaag ccagtggatg aaaaatattt cacccttaag atccgtgggc atgaatgttt 960
caagatgttc ctagagttga atgaggcatt ggagctgaag gatgcccagg ctgggaagca 1020
gccagagggg agcagggctc aatgcagcct tccaaactct aagaaagggg aatctaccac 1080
ccactgtaaa aaactaatgt tcaagagaga ggggcctgac tcagactga 1129
<210> 13
<211> 360
<212> PRT
<213> Loxodonta africana
<400> 13
Met Glu Glu Pro Lys Ser Asp Leu Ser Thr Glu Leu Pro Leu Ser Gln
1 5 10 15
Glu Thr Phe Ser Tyr Leu Gly Lys Leu Leu Pro Glu Lys Leu Val Leu
20 25 30
Ser Pro Ser Leu Ser Pro Ala Ala Glu Ala Val Asp Asp Leu Leu Leu
35 40 45
Pro Glu Asp Ala Ala Asp Cys Leu Glu Ser Gln Ala Gly Ala Gln Glu
50 55 60
Ile Ser Ala Ala Pro Ala Pro Ala Thr Leu Thr Pro Ala Thr Ser Trp
65 70 75 80
Thr Leu Ser Ser Ser Val Pro Ser Gln Lys Thr Tyr Cys Ser Asn Cys
85 90 95
Gly Phe Arg Leu Gly Phe Leu His Ser Gly Thr Ala Lys Ser Val Thr
100 105 110
Cys Met Tyr Ser Pro Gly Leu Asn Lys Leu Phe Cys Gln Leu Ala Lys
115 120 125
Thr Cys Pro Val Gln Pro Leu Ser Ser Pro Pro His Pro Ser Thr Cys
130 135 140
Val His Thr Met Ala Ile Tyr Gln Met Ser Ala Tyr Asp Arg Gly Arg
145 150 155 160
Ala Ala Leu Pro Pro Pro Val Leu Leu Leu Tyr Arg Trp Pro Gly Arg
165 170 175
Ser Ser Ala Ser Tyr Pro Gly Gly Arg Asn Pro Ala Cys Tyr Leu Asp
180 185 190
Thr Ile Thr Leu Gln His Ser Val Gly Tyr Pro Met Ser Tyr Leu Arg
195 200 205
Ser Val Leu Thr Thr Thr Ile His Phe Asn Phe Met Cys Ser Arg Leu
210 215 220
Leu His Gly Gly Gly Asn Pro Ser Ser Pro Ser Ser His Trp Lys Thr
225 230 235 240
Pro Met Val Ile Cys Asp Thr Thr Val Ser Arg Cys Ile Phe Val Leu
245 250 255
Phe Trp Glu Arg Gln Met Tyr Arg Gly Arg Lys Phe Pro Gln Gln Val
260 265 270
Gly Ala Thr Leu Glu Asp His Val Ser Thr Ala His Gln His Gln Leu
275 280 285
Leu Tyr Ala Lys Glu Glu Ala Ser Gly Lys Ile Phe His Pro Asp Pro
290 295 300
Trp Ala Met Phe Gln Asp Val Pro Arg Val Glu Gly Ile Gly Ala Glu
305 310 315 320
Gly Cys Pro Gly Trp Glu Ala Ala Arg Gly Glu Gln Gly Ser Met Gln
325 330 335
Pro Ser Lys Leu Glu Arg Gly Ile Tyr His Pro Leu Lys Thr Asn Val
340 345 350
Gln Glu Arg Gly Ala Leu Arg Leu
355 360
<210> 14
<211> 1129
<212> DNA
<213> Loxodonta africana
<400> 14
atggaggagc ccaagtcaga tctcagtact gagctccctc tgagtcaaga gactttttca 60
tacttgggga aactccttcc tgagaagctg gttctgtccc cctcactgtc cccagcagcg 120
gaggcagtag acgatctgct gctcccagga gatgctgcag actgcctaga aagccaagct 180
ggggctcaag gaatatcagc agcccctgca ccagccaccc ttacaccagc cacctcctgg 240
acactctcat cctctgtccc ttcccagaag acctactgca gcaactgtgg tttccgtctt 300
ggcttcctgc attctgggac agccaagtct gtcacctgca tgtactcccc tggccttaac 360
aagctgtttt gccagctggc aaagacctgt ccagtgcagc cgtagctcag ctcaccaccc 420
caccccagca cctgtgttca caccatggcc atctaccaga cgtcagcata tgacagaggt 480
ggtgcagcac tgcccccacc ttgagtgctg ctccgactat agcgatggcc tggccgctcc 540
tcagcatctt atccaggtgg gaggaatcct gcgtgctgat atttgtagga caccatcact 600
cttcgacata gtgtggggta ccctatgagc tacctcaggt cggttctgac taccaccatc 660
cacttcaact tcatgtgtag cagctcctgc gtgggggcgg gaaacccatc ctcaccatca 720
tcacactgga agactccgat ggtaatctgc taggacacaa cagtttcgag gtgcatattt 780
gtactgttct gggagagaca gacgtacaga ggaagaaaat ttccacaaca agtgggagcc 840
accctctgag aggatcacta agtaagcact gcacaccagc accagctcct ctaccgagcc 900
aaagaagaag ccagtggatg aaaaatattt cacccttaag atccgtgggc atgaatgctt 960
caagatgttc ctagagttga atgaggcatt ggagctgaag gatgcccagg ctgggaagca 1020
gccagagggg agcagggctc aatgcagcct tccaaactct aagaaagggg aatctaccac 1080
ccactgtaaa aaactaatgt tcaagagaga ggggcctgac tcagactga 1129
<210> 15
<211> 361
<212> PRT
<213> Loxodonta africana
<400> 15
Met Glu Glu Pro Lys Ser Asp Leu Ser Thr Glu Leu Pro Leu Ser Gln
1 5 10 15
Glu Thr Phe Ser Tyr Leu Gly Lys Leu Leu Pro Glu Lys Leu Val Leu
20 25 30
Ser Pro Ser Leu Ser Pro Ala Ala Glu Ala Val Asp Asp Leu Leu Leu
35 40 45
Pro Gly Asp Ala Ala Asp Cys Leu Glu Ser Gln Ala Gly Ala Gln Gly
50 55 60
Ile Ser Ala Ala Pro Ala Pro Ala Thr Leu Thr Pro Ala Thr Ser Trp
65 70 75 80
Thr Leu Ser Ser Ser Val Pro Ser Gln Lys Thr Tyr Cys Ser Asn Cys
85 90 95
Gly Phe Arg Leu Gly Phe Leu His Ser Gly Thr Ala Lys Ser Val Thr
100 105 110
Cys Met Tyr Ser Pro Gly Leu Asn Lys Leu Phe Cys Gln Leu Ala Lys
115 120 125
Thr Cys Pro Val Gln Pro Leu Ser Ser Pro Pro His Pro Ser Thr Cys
130 135 140
Val His Thr Met Ala Ile Tyr Gln Thr Ser Ala Tyr Asp Arg Gly Gly
145 150 155 160
Ala Ala Leu Pro Pro Pro Val Leu Leu Arg Leu Arg Trp Pro Gly Arg
165 170 175
Ser Ser Ala Ser Tyr Pro Gly Gly Arg Asn Pro Ala Cys Tyr Leu Asp
180 185 190
Thr Ile Thr Leu Arg His Ser Val Gly Tyr Pro Met Ser Tyr Leu Arg
195 200 205
Ser Val Leu Thr Thr Thr Ile His Phe Asn Phe Met Cys Ser Ser Ser
210 215 220
Cys Val Gly Ala Gly Asn Pro Ser Ser Pro Ser Ser His Trp Lys Thr
225 230 235 240
Pro Met Val Ile Cys Asp Thr Thr Val Ser Arg Cys Ile Phe Val Leu
245 250 255
Phe Trp Glu Arg Gln Thr Tyr Arg Gly Arg Lys Phe Pro Gln Gln Val
260 265 270
Gly Ala Thr Leu Glu Asp His Val Ser Thr Ala His Gln His Gln Leu
275 280 285
Leu Tyr Arg Ala Lys Glu Glu Ala Ser Gly Lys Ile Phe His Pro Asp
290 295 300
Pro Trp Ala Met Leu Gln Asp Val Pro Arg Val Glu Gly Ile Gly Ala
305 310 315 320
Glu Gly Cys Pro Gly Trp Glu Ala Ala Arg Gly Glu Gln Gly Ser Met
325 330 335
Gln Pro Ser Lys Leu Glu Arg Gly Ile Tyr His Pro Leu Lys Thr Asn
340 345 350
Val Gln Glu Arg Gly Ala Leu Arg Leu
355 360
<210> 16
<211> 1129
<212> DNA
<213> Loxodonta africana
<400> 16
atggaggagc ctcagtcaga tctcagcact gagctccctc tgagtcaaga gacgttttca 60
tacttgggga aactccttcc tgagaagctg gttctgtccc cctcactgtc cccagaagcg 120
gaggcagtag acaatctgct actcccagaa gatgctgcag actggctaga aagccaagct 180
ggggctcaag gaatatcaga agcccctaca ctagccacct cctggatgct gtcatcctct 240
gtcccttctc agaagacctg cccagcacct atcgtttctg tctgggcttc ttgcattctg 300
ggacagccaa gtccgtcacc tacacatact cccctgaact taacatgctg ttttgccagc 360
tggcaaaggc ctgcccagtg cagctgtggg tcacctcaac acccccgccc agcacctgtg 420
ttcacaccat ggccatctac cagacgtcag catatgatgg aggtcatgaa gcactgccgc 480
caccttgagt gccgctctga ctatagcaat tgcttggacc ctcctcagca cctcatccag 540
tgggaggaaa cctgcatgct gagtatttgg aggacaccat cactctatga catagtgtgg 600
ggtgccctag tagccaccag aggtcggttc tgactaccac catccacttc aacttcatgt 660
gtaacagctc ctgcatgggg ggcaggaacc tatcctcacc atcatcacac tggaagactc 720
caacggtaat ccgctgggac acaacagttt cgaggtgcat atttgtacct gtcctgggag 780
acacagatgt acagaggaag acagtttcca caagaagtgg gagccttgcc ctgagccagc 840
ctctgggaag gatcactaag cgaacactgc ccaccagcac cagctcctct accaagccaa 900
agaagaagcc actggataaa aaatacttca cccttcagat ccatgggcat gaatgattca 960
agatgttcct aaagctcaac gaggccttgg agctgaagga tgcccaggct gggaggcagc 1020
cagaggggag cagggctcaa cccagccttc ccaagtctaa gaaaaggcaa tctacctcct 1080
gccataaaaa aaactaatgt tctagagaga gcagcctgac tcagactga 1129
<210> 17
<211> 370
<212> PRT
<213> Loxodonta africana
<400> 17
Met Glu Glu Pro Gln Ser Asp Leu Ser Thr Glu Leu Pro Leu Ser Gln
1 5 10 15
Glu Thr Phe Ser Tyr Leu Gly Lys Leu Leu Pro Glu Lys Leu Val Leu
20 25 30
Ser Pro Ser Leu Ser Pro Glu Ala Glu Ala Val Asp Asn Leu Leu Leu
35 40 45
Pro Glu Asp Ala Ala Asp Trp Leu Glu Ser Gln Ala Gly Ala Gln Gly
50 55 60
Ile Ser Glu Ala Pro Thr Leu Ala Thr Ser Trp Met Leu Ser Ser Ser
65 70 75 80
Val Pro Ser Gln Lys Thr Cys Pro Ala Pro Ile Val Ser Val Trp Ala
85 90 95
Ser Cys Ile Leu Gly Gln Pro Ser Pro Ser Pro Thr His Thr Pro Leu
100 105 110
Asn Leu Thr Cys Cys Phe Ala Ser Trp Gln Arg Pro Ala Gln Cys Ser
115 120 125
Cys Gly Ser Pro Gln His Pro Arg Pro Ala Pro Val Phe Thr Pro Trp
130 135 140
Pro Ser Thr Arg Arg Gln His Met Met Glu Val Met Lys His Cys Arg
145 150 155 160
His Leu Glu Cys Arg Ser Asp Tyr Ser Asn Cys Leu Asp Pro Pro Gln
165 170 175
His Leu Ile Gln Trp Glu Glu Thr Cys Met Leu Ser Ile Trp Arg Thr
180 185 190
Pro Ser Leu Tyr Asp Ile Val Trp Gly Ala Leu Val Ala Thr Arg Gly
195 200 205
Arg Phe Leu Pro Pro Ser Thr Ser Thr Ser Cys Val Thr Ala Pro Ala
210 215 220
Trp Gly Ala Gly Thr Tyr Pro His His His His Thr Gly Arg Leu Gln
225 230 235 240
Arg Ser Ala Gly Thr Gln Gln Phe Arg Gly Ala Tyr Leu Tyr Leu Ser
245 250 255
Trp Glu Thr Gln Met Tyr Arg Gly Arg Gln Phe Pro Gln Glu Val Gly
260 265 270
Ala Leu Pro Ala Ser Leu Trp Glu Gly Ser Leu Ser Glu His Cys Pro
275 280 285
Pro Ala Pro Ala Pro Leu Pro Ser Gln Arg Arg Ser His Trp Ile Lys
290 295 300
Asn Thr Ser Pro Phe Arg Ser Met Gly Met Asn Asp Ser Arg Cys Ser
305 310 315 320
Ser Ser Thr Arg Pro Trp Ser Arg Met Pro Arg Leu Gly Gly Ser Gln
325 330 335
Arg Gly Ala Gly Leu Asn Pro Ala Phe Pro Ser Leu Arg Lys Gly Asn
340 345 350
Leu Pro Pro Ala Ile Lys Lys Thr Asn Val Leu Glu Arg Ala Ala Leu
355 360 365
Arg Leu
370
<210> 18
<211> 1126
<212> DNA
<213> Loxodonta africana
<400> 18
atggaggagc ctctgtcaga tctcagcact gagctccctc tgagtcaaga gacgttttca 60
tacttgggga aactccttcc tgagaagctg gttctgtccc cctcactgtc cccagcagcg 120
gaggcagtag acgatctgct actcccagaa gatgctgcag actggctaga aagccaagct 180
ggggctcaag gaatatcaga agcccctaca ctagccacct cctggacgct gtcatcctct 240
gtcccttctc aaaagaccta cccagcacct atcgtttctg tctgggcttc ttgcattctg 300
ggacagccaa gtctgtcacc tacacgtact cccctgaact taacatgctg ttttgccagc 360
tggcaaaggc ctgtccagtg cagccgtggg tcacctcaac aaccccgccc agcacctgtg 420
ttcacaccat ggccatctac cagacgtcag catatgatgg aggtcgtgaa gcactgcccc 480
caccttgagt gccgctgtga ctatagcgat tgcttggacc ctcctcagca cctcatccag 540
tgggaggaaa cctgcatgct gagtatttgg aggacaccat cactctatga catagtgtgg 600
ggtgccctat gagccaccag aggtcggttc tgactaccac catccacttc aacttcatgt 660
gtaacagctc ctgcatgggg ggcaggaacc catcctcacc atcatcactc tggaatactc 720
caatggtaat ccgctgggac acaacagttt cgaggtgcat atttgtacct gtcctgggag 780
acacagatgt acagaggaag acaatttcca gaagaagtgg gagccttgcc ctgagccacc 840
ctctgggagg atcactaagc aaacactgcc caccagcacc agctcctcta tcaagccaaa 900
gaagaagcca ctggatgaaa aatacttcac ccttcagatc catgggcatg aatgtttcaa 960
gatgttccta aagctcaacg aggccttgga gctgaaggat gcccaggctg ggaagcaacc 1020
aggggggagc agggctcaat ccagccttcc caagtctaag aaaaggcaat ctatctccca 1080
ccataaaaaa ataatgttca agagagagca gcctgactca gactga 1126
<210> 19
<211> 365
<212> PRT
<213> Loxodonta africana
<400> 19
Met Glu Glu Pro Leu Ser Asp Leu Ser Thr Glu Leu Pro Leu Ser Gln
1 5 10 15
Glu Thr Phe Ser Tyr Leu Gly Lys Leu Leu Pro Glu Lys Leu Val Leu
20 25 30
Ser Pro Ser Leu Ser Pro Ala Ala Glu Ala Val Asp Asp Leu Leu Leu
35 40 45
Pro Glu Asp Ala Ala Asp Trp Leu Glu Ser Gln Ala Gly Ala Gln Gly
50 55 60
Ile Ser Glu Ala Pro Thr Leu Ala Thr Ser Trp Thr Leu Ser Ser Ser
65 70 75 80
Val Pro Ser Gln Lys Thr Tyr Pro Ala Pro Ile Val Ser Val Trp Ala
85 90 95
Ser Cys Ile Leu Gly Gln Pro Ser Leu Ser Pro Thr Arg Thr Pro Leu
100 105 110
Asn Leu Thr Cys Cys Phe Ala Ser Trp Gln Arg Pro Val Gln Cys Ser
115 120 125
Arg Gly Ser Pro Gln Gln Pro Arg Pro Ala Pro Val Phe Thr Pro Trp
130 135 140
Pro Ser Thr Arg Arg Gln His Met Met Glu Val Val Lys His Cys Pro
145 150 155 160
His Leu Glu Cys Arg Cys Asp Tyr Ser Asp Cys Leu Asp Pro Pro Gln
165 170 175
His Leu Ile Gln Trp Glu Glu Thr Cys Met Leu Ser Ile Trp Arg Thr
180 185 190
Pro Ser Leu Tyr Asp Ile Val Trp Gly Ala Leu Ala Thr Arg Gly Arg
195 200 205
Phe Leu Pro Pro Ser Thr Ser Thr Ser Cys Val Thr Ala Pro Ala Trp
210 215 220
Gly Ala Gly Thr His Pro His His His His Ser Gly Ile Leu Gln Trp
225 230 235 240
Ser Ala Gly Thr Gln Gln Phe Arg Gly Ala Tyr Leu Tyr Leu Ser Trp
245 250 255
Glu Thr Gln Met Tyr Arg Gly Arg Gln Phe Pro Glu Glu Val Gly Ala
260 265 270
Leu Pro Ala Thr Leu Trp Glu Asp His Ala Asn Thr Ala His Gln His
275 280 285
Gln Leu Leu Tyr Gln Ala Lys Glu Glu Ala Thr Gly Lys Ile Leu His
290 295 300
Pro Ser Asp Pro Trp Ala Met Phe Gln Asp Val Pro Lys Ala Gln Arg
305 310 315 320
Gly Leu Gly Ala Glu Gly Cys Pro Gly Trp Glu Ala Thr Arg Gly Glu
325 330 335
Gln Gly Ser Ile Gln Pro Ser Gln Val Glu Lys Ala Ile Tyr Leu Pro
340 345 350
Pro Lys Asn Asn Val Gln Glu Arg Ala Ala Leu Arg Leu
355 360 365
<210> 20
<211> 1126
<212> DNA
<213> Loxodonta africana
<400> 20
atggaggagc ctcagtcaga tctcagcact gagctccctc tgagtcaaga gacattttca 60
tacttgggga aactccttcc tgagaagctg gttctgtccc cctcactgtc cccagcagcg 120
gaggcagtag atgatctgct actcccagaa gatgctgcag actggctaga aagccaagct 180
ggggctcaag gaatatcaga agcccctaca ctagccacct cctggacgct gtcatcctct 240
gtcccttctc agaagaccta cccagcacct atcgtttctg tctgggcttc ttgcattctg 300
ggacagccaa gtctgtcacc tacacgtact cccctgaact taacatgctg ttttgccggc 360
tggcaaaggc ctgtccagtg cagctgtggg tcacctcaac acccccgccc agcacctgtg 420
ttcacaccat ggccatctac cagacgtcag catatgatgg aggtcgtgaa gcactgcccc 480
caccttgagt gccgctgtga ctatagcgat tgcttggacc ctcctcagca cctcatccag 540
taggaggaaa cctgcatgct gagtatttgg aggacaccat cactctatga catagtgtgg 600
ggtgccctag gagccaccag aggtcggttc tgactaccac catccacttc aacttcatgt 660
gtaacagctc ctgcatgggg ggcatgaacc catcctcacc atcatcactc tggaatactc 720
caatggtaat ccgctgggac acaacagttt cgaggtgcat atttgtacct gtcctgggag 780
acacagatgt acagaggaag acaatttcca gaagaagtgg gagccttgcc ctgagccacc 840
ctctgggagg atcactaagc aaacactgcc caccagcacc agctcctcta tcaagccaaa 900
gaagaagcca ctggatgaaa aatacttcac ccttcagatc catggccatg aatgtttcaa 960
gatgttccta aagctcaacg aggccttgga gctgaaggat gcccaggctg ggaagcaacc 1020
agggggaagc agggctcaat ccagccttcc caagtctaag aaaaggcaat ctatctccca 1080
ccataaaaaa ctaatgttca agaaagagca gcctgactca gactga 1126
<210> 21
<211> 364
<212> PRT
<213> Loxodonta africana
<400> 21
Met Glu Glu Pro Gln Ser Asp Leu Ser Thr Glu Leu Pro Leu Ser Gln
1 5 10 15
Glu Thr Phe Ser Tyr Leu Gly Lys Leu Leu Pro Glu Lys Leu Val Leu
20 25 30
Ser Pro Ser Leu Ser Pro Ala Ala Glu Ala Val Asp Asp Leu Leu Leu
35 40 45
Pro Glu Asp Ala Ala Asp Trp Leu Glu Ser Gln Ala Gly Ala Gln Gly
50 55 60
Ile Ser Glu Ala Pro Thr Leu Ala Thr Ser Trp Thr Leu Ser Ser Ser
65 70 75 80
Val Pro Ser Gln Lys Thr Tyr Pro Ala Pro Ile Val Ser Val Trp Ala
85 90 95
Ser Cys Ile Leu Gly Gln Pro Ser Leu Ser Pro Thr Arg Thr Pro Leu
100 105 110
Asn Leu Thr Cys Cys Phe Ala Gly Trp Gln Arg Pro Val Gln Cys Ser
115 120 125
Cys Gly Ser Pro Gln His Pro Arg Pro Ala Pro Val Phe Thr Pro Trp
130 135 140
Pro Ser Thr Arg Arg Gln His Met Met Glu Val Val Lys His Cys Pro
145 150 155 160
His Leu Glu Cys Arg Cys Asp Tyr Ser Asp Cys Leu Asp Pro Pro Gln
165 170 175
His Leu Ile Gln Glu Glu Thr Cys Met Leu Ser Ile Trp Arg Thr Pro
180 185 190
Ser Leu Tyr Asp Ile Val Trp Gly Ala Leu Gly Ala Thr Arg Gly Arg
195 200 205
Phe Leu Pro Pro Ser Thr Ser Thr Ser Cys Val Thr Ala Pro Ala Trp
210 215 220
Gly Ala Thr His Pro His His His His Ser Gly Ile Leu Gln Trp Ser
225 230 235 240
Ala Gly Thr Gln Gln Phe Arg Gly Ala Tyr Leu Tyr Leu Ser Trp Glu
245 250 255
Thr Gln Met Tyr Arg Gly Arg Gln Phe Pro Glu Glu Val Gly Ala Leu
260 265 270
Pro Ala Thr Leu Trp Glu Asp His Ala Asn Thr Ala His Gln His Gln
275 280 285
Leu Leu Tyr Gln Ala Lys Glu Glu Ala Thr Gly Lys Ile Leu His Pro
290 295 300
Ser Asp Pro Trp Pro Met Phe Gln Asp Val Pro Lys Ala Gln Arg Gly
305 310 315 320
Leu Gly Ala Glu Gly Cys Pro Gly Trp Glu Ala Thr Arg Gly Lys Gln
325 330 335
Gly Ser Ile Gln Pro Ser Gln Val Glu Lys Ala Ile Tyr Leu Pro Pro
340 345 350
Lys Thr Asn Val Gln Glu Arg Ala Ala Leu Arg Leu
355 360
<210> 22
<211> 1126
<212> DNA
<213> Loxodonta africana
<400> 22
gtggaggagc ctcagtcaga tctgagcatt gagctccctc tgagtcaaga gacattttca 60
tacttgggga aactcctttc tgagaagctg gttctatccc cctcactgtc cccagcagcg 120
gaggcagtag tcaatctgct actcccagaa gatgctgcag actggctaga aagccaaggt 180
ggggctcaag gaatatcaga agcacctaca ctagccacct cctggacgct gtcatcctct 240
gttccttctc agaagaccta cccagcacct atcatttctg tctgggcttc ttgcattctg 300
ggacagccaa gtccgtcacc tacacgtact cccctgaact taacatgctg ttttgccagc 360
tggcaaaggc ctgtccagtg cagccgtggg tcacctcaac acccccgccc agcacctgtg 420
ttcacaccat ggccatctac cagacatcag catatgatgg aggtcgtgaa gcactgcccc 480
caccttgagt gccgctctga ctatagcgat tgcttggacc ctcctcagca cctcatgcag 540
tgggaggaaa cctgcatgct gagtatttgg aggacaccat cactctatga catagtgtgg 600
ggtgccctag gagccaccag aggtcggttc tgactaccac catccacttc aacttcatgt 660
gtaacagctc ctgcatgggg cgcatgaacc cattctcacc attatgacaa tggaagactc 720
caatggtaat ccgctgggac acaacagttt cgaggtgcat atttgtacct gtcctgggag 780
acacagatgt acagaggaag acaatttcca caacaagtgg gagccttgcc ctgagccacc 840
ctctgggagg atcactacgc aaacactgcc caccagcacc agctcctcta cgaagccaaa 900
gaagaagcca ctggatgaaa aatacttcac ccttcagatc catgggcatg aatgtttcaa 960
gatgttccta aagctcaacg aggccttgga gctgaaggat gcccaggctg ggaagcagcc 1020
agaggggagc agggctcaat ctagccttcc caagtctaag aaaaggcaat ctacctcctg 1080
ccataaaaaa ctaatgttca agagagagca gcctgactca gactga 1126
<210> 23
<211> 365
<212> PRT
<213> Loxodonta africana
<400> 23
Val Glu Glu Pro Gln Ser Asp Leu Ser Ile Glu Leu Pro Leu Ser Gln
1 5 10 15
Glu Thr Phe Ser Tyr Leu Gly Lys Leu Leu Ser Glu Lys Leu Val Leu
20 25 30
Ser Pro Ser Leu Ser Pro Ala Ala Glu Ala Val Val Asn Leu Leu Leu
35 40 45
Pro Glu Asp Ala Ala Asp Trp Leu Glu Ser Gln Gly Gly Ala Gln Gly
50 55 60
Ile Ser Glu Ala Pro Thr Leu Ala Thr Ser Trp Thr Leu Ser Ser Ser
65 70 75 80
Val Pro Ser Gln Lys Thr Tyr Pro Ala Pro Ile Ile Ser Val Trp Ala
85 90 95
Ser Cys Ile Leu Gly Gln Pro Ser Pro Ser Pro Thr Arg Thr Pro Leu
100 105 110
Asn Leu Thr Cys Cys Phe Ala Ser Trp Gln Arg Pro Val Gln Cys Ser
115 120 125
Arg Gly Ser Pro Gln His Pro Arg Pro Ala Pro Val Phe Thr Pro Trp
130 135 140
Pro Ser Thr Arg His Gln His Met Met Glu Val Val Lys His Cys Pro
145 150 155 160
His Leu Glu Cys Arg Ser Asp Tyr Ser Asp Cys Leu Asp Pro Pro Gln
165 170 175
His Leu Met Gln Trp Glu Glu Thr Cys Met Leu Ser Ile Trp Arg Thr
180 185 190
Pro Ser Leu Tyr Asp Ile Val Trp Gly Ala Leu Gly Ala Thr Arg Gly
195 200 205
Arg Phe Leu Pro Pro Ser Thr Ser Thr Ser Cys Val Thr Ala Pro Ala
210 215 220
Trp Gly Ala Thr His Ser His His Tyr Asp Asn Gly Arg Leu Gln Trp
225 230 235 240
Ser Ala Gly Thr Gln Gln Phe Arg Gly Ala Tyr Leu Tyr Leu Ser Trp
245 250 255
Glu Thr Gln Met Tyr Arg Gly Arg Gln Phe Pro Gln Gln Val Gly Ala
260 265 270
Leu Pro Ala Thr Leu Trp Glu Asp His Tyr Ala Asn Thr Ala His Gln
275 280 285
His Gln Leu Leu Tyr Glu Ala Lys Glu Glu Ala Thr Gly Lys Ile Leu
290 295 300
His Pro Ser Asp Pro Trp Ala Met Phe Gln Asp Val Pro Lys Ala Gln
305 310 315 320
Arg Gly Leu Gly Ala Glu Gly Cys Pro Gly Trp Glu Ala Ala Arg Gly
325 330 335
Glu Gln Gly Ser Ile Pro Ser Gln Val Glu Lys Ala Ile Tyr Leu Leu
340 345 350
Pro Lys Thr Asn Val Gln Glu Arg Ala Ala Leu Arg Leu
355 360 365
<210> 24
<211> 1126
<212> DNA
<213> Loxodonta africana
<400> 24
atggaggagc ctcagtcaga tctcagcact gagctccctc tgagtcaaga gacgttttca 60
tacttgggga aactccttcc tgagaagctg gttctatccc cctcactgtc cccagcagcg 120
gaggcagtag tcaatctgct actcccagaa gatgctgcag actggctaga aagccaagct 180
ggggctcaag gaatatcaga agcgcctaca ctagccacct cctggacgct gtcatcctct 240
gttccttctc agaagaccta cccagcacct atcatttctg tctgggcttc ttgcattctg 300
ggacagccaa gtccgtcacc tacacgtact cccctgaact taacatgctg ttttgccagc 360
tggcaaaggc ctgtccagtg cagccatggg tcacctcaac acccccgccc agcacctgtg 420
ttcacaccat ggccatctac cagacatcag catatgatgg aggtcgtgaa gcactgcccc 480
caccttgagt gccgctctaa ctatagcgat tgcttggacc ctactcagca cctcatgcag 540
tgggaggaaa cctgcatgct gagtatttgg aggacaccat cactctatga catagtgtgg 600
ggtgccctag gagccaccag aggtcggttc tgactaccac catccacttc aacttcatgt 660
gtaacagctc ctgcatgggg cgcatgaacc cattctcacc attatgacaa tggaagactc 720
caatggtaat ccgctgggac acaacagttt cgaggtgcat atttgtacct gtcctgggag 780
acacagatgt acagaggaag acaatttcca caacaagtgg gagccttgcc ctgagccacc 840
ctctgggagg atcactacgc aaacactgcc caccagcacc agctcctcta cgaagccaaa 900
gaagaagcca ctggatgaaa aatacttcac ccttcagatc catgggcatg aatgtttcaa 960
gatgttccta aagctcaatg aggccttgga gctgaaggat gcccaggccg ggaaacagcc 1020
agaggggagc agggctcaat ctagccttcc caagtctaag aaaaggcaat ctacctcccg 1080
ccataaaaaa ctaatgttca agagagagca gcctgactca gactga 1126
<210> 25
<211> 364
<212> PRT
<213> Loxodonta africana
<400> 25
Met Glu Glu Pro Gln Ser Asp Leu Ser Thr Glu Leu Pro Leu Ser Gln
1 5 10 15
Glu Thr Phe Ser Tyr Leu Gly Lys Leu Leu Pro Glu Lys Leu Val Leu
20 25 30
Ser Pro Ser Leu Ser Pro Ala Ala Glu Ala Val Val Asn Leu Leu Leu
35 40 45
Pro Glu Asp Ala Ala Asp Trp Leu Glu Ser Gln Ala Gly Ala Gln Gly
50 55 60
Ile Ser Glu Ala Pro Thr Leu Ala Thr Ser Trp Thr Leu Ser Ser Ser
65 70 75 80
Val Pro Ser Gln Lys Thr Tyr Pro Ala Pro Ile Ile Ser Val Trp Ala
85 90 95
Ser Cys Ile Leu Gly Gln Pro Ser Pro Ser Pro Thr Arg Thr Pro Leu
100 105 110
Asn Leu Thr Cys Cys Phe Ala Ser Trp Gln Arg Pro Val Gln Cys Ser
115 120 125
His Gly Ser Pro Gln His Pro Arg Pro Ala Pro Val Phe Thr Pro Trp
130 135 140
Pro Ser Thr Arg His Gln His Met Met Glu Val Val Lys His Cys Pro
145 150 155 160
His Leu Glu Cys Arg Ser Asn Tyr Ser Asp Cys Leu Asp Pro Thr Gln
165 170 175
His Leu Met Gln Trp Glu Glu Thr Cys Met Leu Ser Ile Trp Arg Thr
180 185 190
Pro Ser Leu Tyr Asp Ile Val Trp Gly Ala Leu Gly Ala Thr Arg Gly
195 200 205
Arg Phe Leu Pro Pro Ser Thr Ser Thr Ser Cys Val Thr Ala Pro Ala
210 215 220
Trp Gly Ala Thr His Ser His His Tyr Asp Asn Gly Arg Leu Gln Trp
225 230 235 240
Ser Ala Gly Thr Gln Gln Phe Arg Gly Ala Tyr Leu Tyr Leu Ser Trp
245 250 255
Glu Thr Gln Met Tyr Arg Gly Arg Gln Phe Pro Gln Gln Val Gly Ala
260 265 270
Leu Pro Ala Thr Leu Trp Glu Asp His Tyr Ala Asn Thr Ala His Gln
275 280 285
His Gln Leu Leu Tyr Glu Ala Lys Glu Glu Ala Thr Gly Lys Ile Leu
290 295 300
His Pro Ser Asp Pro Trp Ala Met Phe Gln Asp Val Pro Lys Ala Gln
305 310 315 320
Gly Leu Gly Ala Glu Gly Cys Pro Gly Arg Glu Thr Ala Arg Gly Glu
325 330 335
Gln Gly Ser Ile Pro Ser Gln Val Glu Lys Ala Ile Tyr Leu Pro Pro
340 345 350
Lys Thr Asn Val Gln Glu Arg Ala Ala Leu Arg Leu
355 360
<210> 26
<211> 1127
<212> DNA
<213> Loxodonta africana
<400> 26
atggaggagc ctcagtcaga tctcagcact gagctccctc tgagtcaagg gacgttttca 60
tacttgggga aactccttcc tgagaagctg gttctgttcc cctcactgtc cccagcagca 120
gaggcaatag acgatctgct actcccagaa gatgctgcag actggctaga aagccaagct 180
ggggctcaag gagtatcaga agcccctaca ctagccacct cctggacgct gtcatcctct 240
gtcccttctc agaagaccta cccagcacct atcgtttctg tctgggcttc ttgcattctg 300
ggacagccaa gtccgtcacc tacacgtact cccctgaact taacatgctg ttttgccagc 360
tggcaaaggc ctgtccagtg cagccgtggg tcacctcaac acccccgccc agcacctgtg 420
ttcacaccat ggccatctac cagacgtcag catatgatgg aggtcacgaa gcactgccgc 480
caccttgagt gccgctctgt actatagcga ttgcttggac cctcctcagc acctcatgca 540
gtgggaggaa acctgcatgc tgagtatttg gaggacacca tcactctatg acatagtgtg 600
gggtgcccta ggagccacca gaggtcagtt ctgactacca ccatccactt caacttcatg 660
tgtaacagct cctgcatggg gggcaggaac ccatcctcac catcatcaca ctggaagact 720
ccaatggtaa tccgctggga cacaacagtt tcgaggtgca tatttgtact tgtcctggga 780
gacacagatg tacagaggaa gacaatttcc agaagaagtg ggagccttgc cctgagccag 840
gctcggggag gatcactaag caaacactgc ccaccagcac cagctcctct accaagccaa 900
agaagaagcc actggatgaa aaatacttca ctcttcagat ccatggccat gaatgtttca 960
agatgttcct aaagctcaac gaggccttgg agctgaagga tgcccaggct gggaagcagc 1020
cagaggggag cagggctcaa tccagccttc ccaagtctaa caaaaggcaa tcttcctccc 1080
gccataaaaa actaatgttc aagagagagc agcctgactc agactga 1127
<210> 27
<211> 370
<212> PRT
<213> Loxodonta africana
<400> 27
Met Glu Glu Pro Gln Ser Asp Leu Ser Thr Glu Leu Pro Leu Ser Gln
1 5 10 15
Gly Thr Phe Ser Tyr Leu Gly Lys Leu Leu Pro Glu Lys Leu Val Leu
20 25 30
Phe Pro Ser Leu Ser Pro Ala Ala Glu Ala Ile Asp Asp Leu Leu Leu
35 40 45
Pro Glu Asp Ala Ala Asp Trp Leu Glu Ser Gln Ala Gly Ala Gln Gly
50 55 60
Val Ser Glu Ala Pro Thr Leu Ala Thr Ser Trp Thr Leu Ser Ser Ser
65 70 75 80
Val Pro Ser Gln Lys Thr Tyr Pro Ala Pro Ile Val Ser Val Trp Ala
85 90 95
Ser Cys Ile Leu Gly Gln Pro Ser Pro Ser Pro Thr Arg Thr Pro Leu
100 105 110
Asn Leu Thr Cys Cys Phe Ala Ser Trp Gln Arg Pro Val Gln Cys Ser
115 120 125
Arg Gly Ser Pro Gln His Pro Arg Pro Ala Pro Val Phe Thr Pro Trp
130 135 140
Pro Ser Thr Arg Arg Gln His Met Met Glu Val Thr Lys His Cys Arg
145 150 155 160
His Leu Glu Cys Arg Ser Val Leu Arg Leu Leu Gly Pro Ser Ser Ala
165 170 175
Pro His Ala Val Gly Gly Asn Leu His Ala Glu Tyr Leu Glu Asp Thr
180 185 190
Ile Thr Leu His Ser Val Gly Cys Pro Arg Ser His Gln Arg Ser Val
195 200 205
Leu Thr Thr Thr Ile His Phe Asn Phe Met Cys Asn Ser Ser Cys Met
210 215 220
Gly Gly Arg Asn Pro Ser Ser Pro Ser Ser His Trp Lys Thr Pro Met
225 230 235 240
Val Ile Arg Trp Asp Thr Thr Val Ser Arg Cys Ile Phe Val Leu Val
245 250 255
Leu Gly Asp Thr Asp Val Gln Arg Lys Thr Ile Ser Arg Arg Ser Gly
260 265 270
Ser Leu Ala Leu Ser Gln Ala Arg Gly Gly Ser Leu Ser Lys His Cys
275 280 285
Pro Pro Ala Pro Ala Pro Leu Pro Ser Gln Arg Arg Ser His Trp Met
290 295 300
Lys Asn Thr Ser Leu Phe Arg Ser Met Ala Met Asn Val Ser Arg Cys
305 310 315 320
Ser Ser Ser Thr Arg Pro Trp Ser Arg Met Pro Arg Leu Gly Ser Ser
325 330 335
Gln Arg Gly Ala Gly Leu Asn Pro Ala Phe Pro Ser Leu Thr Lys Gly
340 345 350
Asn Leu Pro Pro Ala Ile Lys Asn Cys Ser Arg Glu Ser Ser Leu Thr
355 360 365
Gln Thr
370
<210> 28
<211> 1126
<212> DNA
<213> Loxodonta africana
<400> 28
atggaggagg ctcagtcaga tctcagcact gagctccctc tgagtcaaga gacgttttca 60
tacttgggga aactccttcc tgagaagctg gttctgttcc cctcactgtc cccagcagca 120
gaggcagtag acgatctgct actcccagaa gatgctgcag actggctaga aagccaagct 180
ggggctcaag gaatatcaga agcccctacg ctagccacct cctggacgct gtcatcctct 240
gtcccttctc agaagaccta cccagcacct atcacttctg tctgggcttc ttgcattctg 300
ggacagccaa gtctgtcacc tacacgtact cccctgaact taacgtgctg ttttgccagc 360
tggcaaaggc ctgtccagtg cagctgtggg tcacctcaac acccccgccc agcacctgtg 420
ttcacaccat ggccatctac cagatgtcag catatgatgg aggtcgtgaa gcactgcccc 480
caccttgagt gccgctctga ctatagcgat tgcttagacc ctcctcagca ccttatccag 540
tgggaggaaa cctgcatgct gagtatttgg aggacaccat cactctatga catagtgtgg 600
ggtgccctag gagccaccag aggtcggttc tgactaccac catccacttc aacttcatgt 660
gtaacagctc ctgcatgggg ggcaggaact catcctcacc atcatcacac tggaagactc 720
caatggtaat ccgctgggac acaacagttt cgaggtgcat atttgtactt gtcctgggag 780
acacagatgt acagaggaag acaatttcca taagaagtgg gagccttgcc ctgagccagg 840
ctcgggaagg atcactaagc gaacactgcc caccagcacc agctcctcta ccaagccaaa 900
gaagaagcca ctggatgaaa aatacttcac tcttcagatc catggccatg aatgcttcaa 960
gatgttccta aagctcaacg aggccttgga gctcaaggat gcccaggctg ggaagcagcc 1020
agaggggaac agggctcaat ccagccttcc caagtctaag aaaaggcaat ctacctcccg 1080
ccataaaaaa cttatgttca agagagagca gcctgactca gactga 1126
<210> 29
<211> 365
<212> PRT
<213> Loxodonta africana
<400> 29
Met Glu Glu Ala Gln Ser Asp Leu Ser Thr Glu Leu Pro Leu Ser Gln
1 5 10 15
Glu Thr Phe Ser Tyr Leu Gly Lys Leu Leu Pro Glu Lys Leu Val Leu
20 25 30
Phe Pro Ser Leu Ser Pro Ala Ala Glu Ala Val Asp Asp Leu Leu Leu
35 40 45
Pro Glu Asp Ala Ala Asp Trp Leu Glu Ser Gln Ala Gly Ala Gln Gly
50 55 60
Ile Ser Glu Ala Pro Thr Leu Ala Thr Ser Trp Thr Leu Ser Ser Ser
65 70 75 80
Val Pro Ser Gln Lys Thr Tyr Pro Ala Pro Ile Thr Ser Val Trp Ala
85 90 95
Ser Cys Ile Leu Gly Gln Pro Ser Leu Ser Pro Thr Arg Thr Pro Leu
100 105 110
Asn Leu Thr Cys Cys Phe Ala Ser Trp Gln Arg Pro Val Gln Cys Ser
115 120 125
Cys Gly Ser Pro Gln His Pro Arg Pro Ala Pro Val Phe Thr Pro Trp
130 135 140
Pro Ser Thr Arg Cys Gln His Met Met Glu Val Val Lys His Cys Pro
145 150 155 160
His Leu Glu Cys Arg Ser Asp Tyr Ser Asp Cys Leu Asp Pro Pro Gln
165 170 175
His Leu Ile Gln Trp Glu Glu Thr Cys Met Leu Ser Ile Trp Arg Thr
180 185 190
Pro Ser Leu Tyr Asp Ile Val Trp Gly Ala Leu Gly Ala Thr Arg Gly
195 200 205
Arg Phe Leu Pro Pro Ser Thr Ser Thr Ser Cys Val Thr Ala Pro Ala
210 215 220
Trp Gly Ala Gly Thr His Pro His His His His Thr Gly Arg Leu Gln
225 230 235 240
Trp Ser Ala Gly Thr Gln Gln Phe Arg Gly Ala Tyr Leu Tyr Leu Ser
245 250 255
Trp Glu Thr Gln Met Tyr Arg Gly Arg Gln Phe Pro Glu Val Gly Ala
260 265 270
Leu Pro Ala Arg Leu Gly Lys Asp His Ala Asn Thr Ala His Gln His
275 280 285
Gln Leu Leu Tyr Gln Ala Lys Glu Glu Ala Thr Gly Lys Ile Leu His
290 295 300
Ser Ser Asp Pro Trp Pro Met Leu Gln Asp Val Pro Lys Ala Gln Arg
305 310 315 320
Gly Leu Gly Ala Gln Gly Cys Pro Gly Trp Glu Ala Ala Arg Gly Glu
325 330 335
Gln Gly Ser Ile Gln Pro Ser Gln Val Glu Lys Ala Ile Tyr Leu Pro
340 345 350
Pro Lys Thr Tyr Val Gln Glu Arg Ala Ala Leu Arg Leu
355 360 365
<210> 30
<211> 1126
<212> DNA
<213> Loxodonta africana
<400> 30
aaggaggagc ctcagtcaga tctcagcact gagctccctc tgagtcaagg gacgttttca 60
tacttgggga aactccttcc tgagaagctg gttctgttcc cctcactgtc cccagcagca 120
gaggcagtag acgatctgct actcccagaa gatgctgcag actggctaga aagccaagct 180
ggggctcaag gaatatcaga agcccctaca ctagccacct cctggacgct gtcatcctct 240
gtcccttctc agaagaccta cccagcacct atcatttctg tctgggcttc ttgcattctg 300
ggacagccaa gtctgtcacc tacacgtact cccctgaact taacatgctg ttttgccagc 360
tggcaaaggc ctgtccagtg cagctgtggg tcacctcaac acccccgccc agcacctgtg 420
ttcacaccat ggccatctac cagacgtcag catatgatgg aggtcgtgaa gcactgcccc 480
caccttgagt gccgctctga ctatagcgat tgcttagacc ctcctcagca ccttatccag 540
tgggaggaaa cctgcatgct gagtatttgg aggacaccat cactctatga catagtgtgg 600
ggtgccctag gagccaccag aggtcggttc tgactaccac catccacttc aacttcatgt 660
gtaacagctc ctgcatgggg ggcaggaacc catcctcacc atcatcacac tggaagactc 720
caatggtaat ccgctgggac acaacagttt cgaggtgcat atttgtactt gtcctgggag 780
acacagatgt acagaggaag acaatttcca taagaagtgg gagccttgcc ctgagccagg 840
ctcggggagg atcactaagc gaacactgcc caccagcacc agctcctcta ccaagccaaa 900
gaagaagcca ctggatgaaa aatacttcac tcttcagatc catggccatg aatgcttcaa 960
gatgttccta aagctcaacg aggccttgga gctcaaggat gcccaggctg ggaagcagcc 1020
agaggggaac agggctcaat ccagccttcc caagtctaag aaaaggcaat ctacctcccg 1080
ccataaaaaa cttatgttca agagagagca gcctgactca gactga 1126
<210> 31
<211> 365
<212> PRT
<213> Loxodonta africana
<400> 31
Lys Glu Glu Pro Gln Ser Asp Leu Ser Thr Glu Leu Pro Leu Ser Gln
1 5 10 15
Gly Thr Phe Ser Tyr Leu Gly Lys Leu Leu Pro Glu Lys Leu Val Leu
20 25 30
Phe Pro Ser Leu Ser Pro Ala Ala Glu Ala Val Asp Asp Leu Leu Leu
35 40 45
Pro Glu Asp Ala Ala Asp Trp Leu Glu Ser Gln Ala Gly Ala Gln Gly
50 55 60
Ile Ser Glu Ala Pro Thr Leu Ala Thr Ser Trp Thr Leu Ser Ser Ser
65 70 75 80
Val Pro Ser Gln Lys Thr Tyr Pro Ala Pro Ile Ile Ser Val Trp Ala
85 90 95
Ser Cys Ile Leu Gly Gln Pro Ser Leu Ser Pro Thr Arg Thr Pro Leu
100 105 110
Asn Leu Thr Cys Cys Phe Ala Ser Trp Gln Arg Pro Val Gln Cys Ser
115 120 125
Cys Gly Ser Pro Gln His Pro Arg Pro Ala Pro Val Phe Thr Pro Trp
130 135 140
Pro Ser Thr Arg Arg Gln His Met Met Glu Val Val Lys His Cys Pro
145 150 155 160
His Leu Glu Cys Arg Ser Asp Tyr Ser Asp Cys Leu Asp Pro Pro Gln
165 170 175
His Leu Ile Gln Trp Glu Glu Thr Cys Met Leu Ser Ile Trp Arg Thr
180 185 190
Pro Ser Leu Tyr Asp Ile Val Trp Gly Ala Leu Gly Ala Thr Arg Gly
195 200 205
Arg Phe Leu Pro Pro Ser Thr Ser Thr Ser Cys Val Thr Ala Pro Ala
210 215 220
Trp Gly Ala Gly Thr His Pro His His His His Thr Gly Arg Leu Gln
225 230 235 240
Trp Ser Ala Gly Thr Gln Gln Phe Arg Gly Ala Tyr Leu Tyr Leu Ser
245 250 255
Trp Glu Thr Gln Met Tyr Arg Gly Arg Gln Phe Pro Glu Val Gly Ala
260 265 270
Leu Pro Ala Arg Leu Gly Glu Asp His Ala Asn Thr Ala His Gln His
275 280 285
Gln Leu Leu Tyr Gln Ala Lys Glu Glu Ala Thr Gly Lys Ile Leu His
290 295 300
Ser Ser Asp Pro Trp Pro Met Leu Gln Asp Val Pro Lys Ala Gln Arg
305 310 315 320
Gly Leu Gly Ala Gln Gly Cys Pro Gly Trp Glu Ala Ala Arg Gly Glu
325 330 335
Gln Gly Ser Ile Gln Pro Ser Gln Val Glu Lys Ala Ile Tyr Leu Pro
340 345 350
Pro Lys Thr Tyr Val Gln Glu Arg Ala Ala Leu Arg Leu
355 360 365
<210> 32
<211> 1126
<212> DNA
<213> Loxodonta africana
<400> 32
atggaggagc ctcagtcaga tctcagcact gagctccctc tgagtcaagg gacgttttca 60
tacttgggga aactccttcc tgagaagctg gttctgttcc cctcactgtc cccagcagca 120
gaggcagtag acgatctgct actcccagaa gatgctgcag actggctaga aagccaagct 180
ggggctcaag gaatatcaga agcccctaca ctagccacct cctggacgct gtcatcctct 240
gtcccttctc agaagaccta cccagcacct atcatttctg tctgggcttc ttgcattctg 300
ggacagccaa gtctgtcacc tacacgtact cccctgaact taacatgctg ttttgccagc 360
tggcaaaggc ctgtccagtg cagctgtggg tcacctcaac atccccgccc agcacctgtg 420
ttcacaccat ggccatctac cagacgtcag catatgatgg aggtcgtgaa gcactgcccc 480
caccttgagt gccgctctga ctatagtgat tgcttagacc ctcctcagca ccttatccag 540
tgggaggaaa cctgcatgct gagcatttgg aggacaccat cactctatga catagtgtgg 600
ggtgccctag gagccaccag aggtcggttc tgactaccac catccacttc aacttcatgt 660
gtaacagctc ctgcatgggg ggcaggaacc catcctcacc atcatcacac tggaagactc 720
caatggtaat ccgctgggac acaacagttt cgaggtgcat atttgtactt gtcctgggag 780
acacagatat acagaggaag acaatttcca taagaagtgg gagccttgcc ctgagccagg 840
ctcggggagg atcactaagt gaacactgcc caccagcacc agctcctcta ccaagccaaa 900
gaagaagcca ctggatgaaa aatacttcac tcttcagatc catggccatg aatgcttcaa 960
gatgttccta aagctcaacg aggccttgga gctcaaggat gcccagactg ggaagcagcc 1020
agaggggaac agggctcaat ccagccttcc caagtctaag aaaaggcaat ctacctcccg 1080
ccataaaaaa cttatgttca acagagagca gcctgactca gactga 1126
<210> 33
<211> 365
<212> PRT
<213> Loxodonta africana
<400> 33
Met Glu Glu Pro Gln Ser Asp Leu Ser Thr Glu Leu Pro Leu Ser Gln
1 5 10 15
Gly Thr Phe Ser Tyr Leu Gly Lys Leu Leu Pro Glu Lys Leu Val Leu
20 25 30
Phe Pro Ser Leu Ser Pro Ala Ala Glu Ala Val Asp Asp Leu Leu Leu
35 40 45
Pro Glu Asp Ala Ala Asp Trp Leu Glu Ser Gln Ala Gly Ala Gln Gly
50 55 60
Ile Ser Glu Ala Pro Thr Leu Ala Thr Ser Trp Thr Leu Ser Ser Ser
65 70 75 80
Val Pro Ser Gln Lys Thr Tyr Pro Ala Pro Ile Ile Ser Val Trp Ala
85 90 95
Ser Cys Ile Leu Gly Gln Pro Ser Leu Ser Pro Thr Arg Thr Pro Leu
100 105 110
Asn Leu Thr Cys Cys Phe Ala Ser Trp Gln Arg Pro Val Gln Cys Ser
115 120 125
Cys Gly Ser Pro Gln His Pro Arg Pro Ala Pro Val Phe Thr Pro Trp
130 135 140
Pro Ser Thr Arg Arg Gln His Met Met Glu Val Val Lys His Cys Pro
145 150 155 160
His Leu Glu Cys Arg Ser Asp Tyr Ser Asp Cys Leu Asp Pro Pro Gln
165 170 175
His Leu Ile Gln Trp Glu Glu Thr Cys Met Leu Ser Ile Trp Arg Thr
180 185 190
Pro Ser Leu Tyr Asp Ile Val Trp Gly Ala Leu Gly Ala Thr Arg Gly
195 200 205
Arg Phe Leu Pro Pro Ser Thr Ser Thr Ser Cys Val Thr Ala Pro Ala
210 215 220
Trp Gly Ala Gly Thr His Pro His His His His Thr Gly Arg Leu Gln
225 230 235 240
Trp Ser Ala Gly Thr Gln Gln Phe Arg Gly Ala Tyr Leu Tyr Leu Ser
245 250 255
Trp Glu Thr Gln Ile Tyr Arg Gly Arg Gln Phe Pro Glu Val Gly Ala
260 265 270
Leu Pro Ala Arg Leu Gly Glu Asp His Val Asn Thr Ala His Gln His
275 280 285
Gln Leu Leu Tyr Gln Ala Lys Glu Glu Ala Thr Gly Lys Ile Leu His
290 295 300
Ser Ser Asp Pro Trp Pro Met Leu Gln Asp Val Pro Lys Ala Gln Arg
305 310 315 320
Gly Leu Gly Ala Gln Gly Cys Pro Asp Trp Glu Ala Ala Arg Gly Glu
325 330 335
Gln Gly Ser Ile Gln Pro Ser Gln Val Glu Lys Ala Ile Tyr Leu Pro
340 345 350
Pro Lys Thr Tyr Val Gln Gln Arg Ala Ala Leu Arg Leu
355 360 365
<210> 34
<211> 1121
<212> DNA
<213> Loxodonta africana
<400> 34
gtggaggagc ctcagtcaga tctcagcact gagctccctc tgagtcaagg gacgttttca 60
tacttgggga aactccttcc tgagaagctg gttctgtccc tctcactgtc cccagcagca 120
gaggcagtag acgatctgct actcccagaa gatgctgcag actggctaga aagccaagct 180
ggggctcaag gagtatcaga agcccctaca ctagccacct cctggacgct gtcatcctct 240
gtcccttctc agaagaccta cccagcacct atcgtttctg tctgggcttc tagcattctg 300
ggacagccca gttcgtcact tacacgtact cccctgaact taacatgctg ttttgccagc 360
tggcaaaggc ctgtccagcg cagctgtggg tcaccctcaa cacccccgcc cagcacctgt 420
gttcacacca tggccatcta ccagacgtca gcatatgatg gaggtcgtga agcactgccc 480
ccaccttgag tgccgctcta actatagcga ttgcttggac cctcctcagc acctcatcca 540
gtgggaggaa acctgcatgc tgagtatttg gaggacacca tcactctatg acatagtgtg 600
gggtgcccta ggagccacca gaggtcggtt ctgactacca ccatccactt catgtgtaac 660
agctcctgca tggggggcag gaagccatcc tcaccatcat cacactggaa gactccaaag 720
gtaatccgct gggacacaac agtttcgagg tgcatatttg tacttgtcct gggagacaca 780
gatatacaga ggaagacaat ttccataaga agtgggagcc ttgccctgag ccaggctcgg 840
ggaggatcac taagcgaaca ctgcccacca gcaccagctc ctctaccaag ccaaagaaga 900
agccactgga tgaaaaatac ttcactcttc agatccatgg ccatgaatgc ttcaagatgt 960
tcctaaagct caacgaggcc ttggagctca aggatgccca ggctgggaag cagccagagg 1020
ggagcagggc tcaatccagc cttcccaagt ctaagaaaag gcaatctacc tcccgccata 1080
aaaaacttat gttcaagaga gagcagcctg actcagactg a 1121
<210> 35
<211> 368
<212> PRT
<213> Loxodonta africana
<400> 35
Val Glu Glu Pro Gln Ser Asp Leu Ser Thr Glu Leu Pro Leu Ser Gln
1 5 10 15
Gly Thr Phe Ser Tyr Leu Gly Lys Leu Leu Pro Glu Lys Leu Val Leu
20 25 30
Ser Leu Ser Leu Ser Pro Ala Ala Glu Ala Val Asp Asp Leu Leu Leu
35 40 45
Pro Glu Asp Ala Ala Asp Trp Leu Glu Ser Gln Ala Gly Ala Gln Gly
50 55 60
Val Ser Glu Ala Pro Thr Leu Ala Thr Ser Trp Thr Leu Ser Ser Ser
65 70 75 80
Val Pro Ser Gln Lys Thr Tyr Pro Ala Pro Ile Val Ser Val Trp Ala
85 90 95
Ser Ser Ile Leu Gly Gln Pro Ser Ser Ser Leu Thr Arg Thr Pro Leu
100 105 110
Asn Leu Thr Cys Cys Phe Ala Ser Trp Gln Arg Pro Val Gln Arg Ser
115 120 125
Cys Gly Ser Pro Ser Thr Pro Pro Pro Ser Thr Cys Val His Thr Met
130 135 140
Ala Ile Tyr Gln Thr Ser Ala Tyr Asp Gly Gly Arg Glu Ala Leu Pro
145 150 155 160
Pro Pro Val Pro Leu Leu Arg Leu Leu Gly Pro Ser Ser Ala Pro His
165 170 175
Pro Val Gly Gly Asn Leu His Ala Glu Tyr Leu Glu Asp Thr Ile Thr
180 185 190
Leu His Ser Val Gly Cys Pro Arg Ser His Gln Arg Ser Val Leu Thr
195 200 205
Thr Thr Ile His Phe Met Cys Asn Ser Ser Cys Met Gly Gly Arg Lys
210 215 220
Pro Ser Ser Pro Ser Ser His Trp Lys Thr Pro Lys Val Ile Arg Trp
225 230 235 240
Asp Thr Thr Val Ser Arg Cys Ile Phe Val Leu Val Leu Gly Asp Thr
245 250 255
Asp Ile Gln Arg Lys Thr Ile Ser Ile Arg Ser Gly Ser Leu Ala Leu
260 265 270
Ser Gln Ala Arg Gly Gly Ser Leu Ser Glu His Cys Pro Pro Ala Pro
275 280 285
Ala Pro Leu Pro Ser Gln Arg Arg Ser His Trp Met Lys Asn Thr Ser
290 295 300
Leu Phe Arg Ser Met Ala Met Asn Ala Ser Arg Cys Ser Ser Ser Thr
305 310 315 320
Arg Pro Trp Ser Ser Arg Met Pro Arg Leu Gly Ser Ser Gln Arg Gly
325 330 335
Ala Gly Leu Asn Pro Ala Phe Pro Ser Leu Arg Lys Gly Asn Leu Pro
340 345 350
Pro Ala Ile Lys Asn Leu Cys Ser Arg Glu Ser Ser Leu Thr Gln Thr
355 360 365
<210> 36
<211> 1127
<212> DNA
<213> Loxodonta africana
<400> 36
atggaggagc ctcagtcaga tctcagcact gagctccctc tgagtcaaga gacgttttca 60
tacttgggga aactccttcc tgagaagctg gttctgttcc cctcactgtc cccagcagca 120
gaggcaatag acgatctgct actcccagaa gatgctgcag actggctaga aagccaagct 180
ggggctcaag gaatatcaga agcctctaca ctagccacct cctggacgct gtcatcctct 240
gtcccttctc agaagaccta cccagcacct atcgtttctg tctgggcttc ttgcattctg 300
ggacagccaa gttcgtcacc tacacgtact cccctgaact taacatgctg ttttgccagc 360
tggcaaaggc ctgtccagtg cagctgtggg tcacctcaac acccccgccc agcacctgtg 420
ttcacaccat ggccatctac cagacgtcag catatgatgg aggtcgtgaa gcattgcccc 480
ccaccttgag tgccgctctg actatagcga ttgcttggac cctcctcagc acctcatcca 540
gtgggaggaa acctgcatgc tgagtatttg gaggacacca tcactctatg acatagtgtg 600
gggtgcccta tgagccacca gaggtcggtt ctgactacca ccatccactt caacttcatg 660
tgtaacagct cctgcatggg gggcaggaag ccatcctcac catcatcaca ctggaagact 720
ccaatggtaa tccgctgaga cacaacagtt tcgaggtgca tatttgtact tgtcctggga 780
gacacagatg tacagaggaa gacaatttcc agaagaagtg ggagccttgc cctgagccag 840
gctcggggag gatcactaag cgaacactgc ccaccagcac cagctcctct accaagccaa 900
agaagaagcc actggatgaa aaatacttca ctcttcagat ccatggccat gaatgcttca 960
agatgttcct aaagctcaac gaggccttgg agttgaagga tgcccaggct gggaagcagc 1020
cagaggggag cagggctcaa tccagccttc ccaagtctaa gaaaaggcaa tctacctccc 1080
gccataaaaa acatatgttc aagagagagc agcctgactc agactga 1127
<210> 37
<211> 368
<212> PRT
<213> Loxodonta africana
<400> 37
Met Glu Glu Pro Gln Ser Asp Leu Ser Thr Glu Leu Pro Leu Ser Gln
1 5 10 15
Glu Thr Phe Ser Tyr Leu Gly Lys Leu Leu Pro Glu Lys Leu Val Leu
20 25 30
Phe Pro Ser Leu Ser Pro Ala Ala Glu Ala Ile Asp Asp Leu Leu Leu
35 40 45
Pro Glu Asp Ala Ala Asp Trp Leu Glu Ser Gln Ala Gly Ala Gln Gly
50 55 60
Ile Ser Glu Ala Ser Thr Leu Ala Thr Ser Trp Thr Leu Ser Ser Ser
65 70 75 80
Val Pro Ser Gln Lys Thr Tyr Pro Ala Pro Ile Val Ser Val Trp Ala
85 90 95
Ser Cys Ile Leu Gly Gln Pro Ser Ser Ser Pro Thr Arg Thr Pro Leu
100 105 110
Asn Leu Thr Cys Cys Phe Ala Ser Trp Gln Arg Pro Val Gln Cys Ser
115 120 125
Cys Gly Ser Pro Gln His Pro Arg Pro Ala Pro Val Phe Thr Pro Trp
130 135 140
Pro Ser Thr Arg Arg Gln His Met Met Glu Val Val Lys His Cys Pro
145 150 155 160
Pro Pro Val Pro Leu Leu Arg Leu Leu Gly Pro Ser Ser Ala Pro His
165 170 175
Pro Val Gly Gly Asn Leu His Ala Glu Tyr Leu Glu Asp Thr Ile Thr
180 185 190
Leu His Ser Val Gly Cys Pro Met Ser His Gln Arg Ser Val Leu Thr
195 200 205
Thr Thr Ile His Phe Asn Phe Met Cys Asn Ser Ser Cys Met Gly Gly
210 215 220
Arg Lys Pro Ser Ser Pro Ser Ser His Trp Lys Thr Pro Met Val Ile
225 230 235 240
Arg Asp Thr Thr Val Ser Arg Cys Ile Phe Val Leu Val Leu Gly Asp
245 250 255
Thr Asp Val Gln Arg Lys Thr Ile Ser Arg Arg Ser Gly Ser Leu Ala
260 265 270
Leu Ser Gln Ala Arg Gly Gly Ser Leu Ser Glu His Cys Pro Pro Ala
275 280 285
Pro Ala Pro Leu Pro Ser Gln Arg Arg Ser His Trp Met Lys Asn Thr
290 295 300
Ser Leu Phe Arg Ser Met Ala Met Asn Ala Ser Arg Cys Ser Ser Ser
305 310 315 320
Thr Arg Pro Trp Ser Arg Met Pro Arg Leu Gly Ser Ser Gln Arg Gly
325 330 335
Ala Gly Leu Asn Pro Ala Phe Pro Ser Leu Arg Lys Gly Asn Leu Pro
340 345 350
Pro Ala Ile Lys Asn Ile Cys Ser Arg Glu Ser Ser Leu Thr Gln Thr
355 360 365
<210> 38
<211> 1126
<212> DNA
<213> Loxodonta africana
<400> 38
atggaagagc ctcagtcaga tctcagcact gagctccctc tgagtcaagg gacgttttca 60
tacttgggga aactccttcc tgagaagctg gttctgttcc cctcactgtc cccagcagca 120
gaggcaatag acgatctact actcccagaa gatgctgcag actggctaga aagccaagct 180
ggggctcaag gaatatcaga agcctctaca ctagccacct cctggacgct gtcatcctct 240
gtcccttctc agaagaccta cccagcacct atcgtttctg tctgggcttc ttgcattctg 300
ggacagccaa gttcgtcacc tagacgtact cccctgaact taacatgctg ttttgccagc 360
tggcaaaggc ctgtccagtg cagctgtggg tcacctcaac acccccgcca agcacctgtg 420
ttcacaccat ggccatctac cagacgtcag catatgatgg aggtcgtgaa gcactgcccc 480
caccttgagt gccgctctga ctatagcgat tgcttggacc ctcctcagca cctcatccag 540
tgggaggaaa cctgcatgct gagtatttgg aggacaccat cactctatga catagcgtgg 600
ggtgccctat gagccaccag aggtcggttc tgactaccac catccacttc aacctcatgt 660
gtaacagctc ctgcatgggg ggcaggaagc catcctcacc atcatcacac tggaagactc 720
caatggtaat ccgctgggac acaacagttt cgaggtgcat atttgtactt gtcctgggag 780
acacagatgt acagaggaag acaatttcca taagaagtgg gagccttgcc ctgagccagg 840
ctcggggagg atcactaagc gaacactgcc caccagcacc agctcctcta tcaagccaaa 900
gaagaagcca ctggatgaaa aatacttcac tcttcagatc catggccatg aatgcttcaa 960
gatgttccta aagctcaacg aggccttgga gctgaaggat gcccaggctg ggaagcagcc 1020
agaggggagc agggctcaat ccagccttcc caagtctaag aaaaggcaat ctacctcccg 1080
ccataaaaaa cttatgttca agagagagca gcctgactca gactga 1126
<210> 39
<211> 364
<212> PRT
<213> Loxodonta africana
<400> 39
Met Glu Glu Pro Gln Ser Asp Leu Ser Thr Glu Leu Pro Leu Ser Gln
1 5 10 15
Gly Thr Phe Ser Tyr Leu Gly Lys Leu Leu Pro Glu Lys Leu Val Leu
20 25 30
Phe Pro Ser Leu Ser Pro Ala Ala Glu Ala Ile Asp Asp Leu Leu Leu
35 40 45
Pro Glu Asp Ala Ala Asp Trp Leu Glu Ser Gln Ala Gly Ala Gln Gly
50 55 60
Ile Ser Glu Ala Ser Thr Leu Ala Thr Ser Trp Thr Leu Ser Ser Ser
65 70 75 80
Val Pro Ser Gln Lys Thr Tyr Pro Ala Pro Ile Val Ser Val Trp Ala
85 90 95
Ser Cys Ile Leu Gly Gln Pro Ser Ser Ser Pro Arg Arg Thr Pro Leu
100 105 110
Asn Leu Thr Cys Cys Phe Ala Ser Trp Gln Arg Pro Val Gln Cys Ser
115 120 125
Cys Gly Ser Pro Gln His Pro Arg Gln Ala Pro Val Phe Thr Pro Trp
130 135 140
Pro Ser Thr Arg Arg Gln His Met Met Glu Val Val Lys His Cys Pro
145 150 155 160
His Leu Glu Cys Arg Ser Asp Tyr Ser Asp Cys Leu Asp Pro Pro Gln
165 170 175
His Leu Ile Gln Trp Glu Glu Thr Cys Met Leu Ser Ile Trp Arg Thr
180 185 190
Pro Ser Leu Tyr Asp Ile Ala Trp Gly Ala Leu Ala Thr Arg Gly Arg
195 200 205
Phe Leu Pro Pro Ser Thr Ser Thr Ser Cys Val Thr Ala Pro Ala Trp
210 215 220
Gly Ala Gly Ser His Pro His His His His Thr Gly Arg Leu Gln Trp
225 230 235 240
Ser Ala Gly Thr Gln Gln Phe Arg Gly Ala Tyr Leu Tyr Leu Ser Trp
245 250 255
Glu Thr Gln Met Tyr Arg Gly Arg Gln Phe Pro Glu Val Gly Ala Leu
260 265 270
Pro Ala Arg Leu Gly Glu Asp His Ala Asn Thr Ala His Gln His Gln
275 280 285
Leu Leu Tyr Gln Ala Lys Glu Glu Ala Thr Gly Lys Ile Leu His Ser
290 295 300
Ser Asp Pro Trp Pro Met Leu Gln Asp Val Pro Lys Ala Gln Arg Gly
305 310 315 320
Leu Gly Ala Glu Gly Cys Pro Gly Trp Glu Ala Ala Arg Gly Glu Gln
325 330 335
Gly Ser Ile Gln Pro Ser Gln Val Glu Lys Ala Ile Tyr Leu Pro Pro
340 345 350
Lys Thr Tyr Val Gln Glu Arg Ala Ala Leu Arg Leu
355 360
<210> 40
<211> 1143
<212> DNA
<213> Loxodonta africana
<400> 40
aagagaggag ccccagtaag atctcagcac tgacttccct ctgagccaag agaccttttc 60
atacttaggg gaactccttc ctgagaagct ggttcagtcc ccctcactgt ccccagcagt 120
ggaggtagtg gatgatctgc tactcacaga agatgttgca gactggctag aaagccaagc 180
tggggctcaa agaatatcag cagcccctgc accacccacc cctacaccag ccacctgctt 240
gaccctgtca tcctctgtcc cttcccagaa gacctaccca acacctatgg tttctgtctg 300
gacttcctac attctgggac agccatttcc gtcacctaca tgtactcccc tgaccttaac 360
aagctgtttt gccagctggc aaagacctgt ccggtgcagc tgtgggtgac ctcaccaccc 420
cggcccagca tctgtgttca caccacagcc atctaccaca agtcagcatg tgacggaggt 480
ggtgcagcac tgcccccacc ttgagtgccg ctctgactat ggcgatggcc tggcccctcc 540
tcagcatctc atccgggggg ggaggaaatc tgcttgccga gtatttggag gacaccatca 600
ctcttcgaca cggtgtgggg tgccctatga accaccagag atcggctctg actaccacca 660
tccaattcaa cttcgtgcgt aacaacttct gcatgggggg caggaatcca tcctcaccat 720
caacacactg gaagactcca aagataatct gctgggacac aacagtttcg aggtgcatat 780
ttgcacctgt cctggtagag acagacgtac agagaaagaa aatttccaca agacgtggga 840
gccttgccat gaaccaccct ctgggaggat cactaagcaa gcactgccca cgagcaccag 900
atcctctacc cagccaaaga agaagccact ggatgaaaaa tacttcaccc atcagatctg 960
tgggcatgaa tgcttcaaga cattcctaga gctgaatgaa gccttggagc tgaggatgcc 1020
cagcctggga agcagccaca ggggagcagg gctcaatcca ggcttctaaa gtctaagaaa 1080
gggccatcta cctcccgcca taaaaaacta atgttcaata gagatgggcc tgactcagac 1140
tga 1143
<210> 41
<211> 366
<212> PRT
<213> Loxodonta africana
<400> 41
Lys Arg Gly Ala Pro Val Arg Ser Gln His Leu Pro Ser Glu Pro Arg
1 5 10 15
Asp Leu Phe Ile Leu Arg Gly Thr Pro Ser Glu Ala Gly Ser Val Pro
20 25 30
Leu Thr Val Pro Ser Ser Gly Gly Ser Gly Ser Ala Thr His Arg Arg
35 40 45
Cys Cys Arg Leu Ala Arg Lys Pro Ser Trp Gly Ser Lys Asn Ile Ser
50 55 60
Ser Pro Cys Thr Thr His Pro Tyr Thr Ser His Leu Leu Asp Pro Val
65 70 75 80
Ile Leu Cys Pro Phe Pro Glu Asp Leu Pro Asn Thr Tyr Gly Phe Cys
85 90 95
Leu Asp Phe Leu His Ser Gly Thr Ala Ile Ser Val Thr Tyr Met Tyr
100 105 110
Ser Pro Asp Leu Asn Lys Leu Phe Cys Gln Leu Ala Lys Thr Cys Pro
115 120 125
Val Gln Leu Trp Val Thr Ser Pro Pro Arg Pro Ser Ile Cys Val His
130 135 140
Thr Thr Ala Ile Tyr His Lys Ser Ala Cys Asp Gly Gly Gly Ala Ala
145 150 155 160
Leu Pro Pro Pro Val Pro Leu Leu Trp Arg Trp Pro Gly Pro Ser Ser
165 170 175
Ala Ser His Pro Gly Gly Glu Glu Ile Cys Leu Pro Ser Ile Trp Arg
180 185 190
Thr Pro Ser Leu Phe Asp Thr Val Trp Gly Ala Leu Thr Thr Arg Asp
195 200 205
Arg Leu Leu Pro Pro Ser Asn Ser Thr Ser Cys Val Thr Thr Ser Ala
210 215 220
Trp Gly Ala Gly Ile His Pro His His Gln His Thr Gly Arg Leu Gln
225 230 235 240
Arg Ser Ala Gly Thr Gln Gln Phe Arg Gly Ala Tyr Leu His Leu Ser
245 250 255
Trp Arg Gln Thr Tyr Arg Glu Arg Lys Phe Pro Gln Asp Val Gly Ala
260 265 270
Leu Pro Thr Thr Leu Trp Glu Asp His Ala Ser Thr Ala His Glu His
275 280 285
Gln Ile Leu Tyr Pro Ala Lys Glu Glu Ala Thr Gly Lys Ile Leu His
290 295 300
Pro Ser Asp Leu Trp Ala Met Leu Gln Asp Ile Pro Arg Ala Glu Ser
305 310 315 320
Leu Gly Ala Glu Asp Ala Gln Pro Gly Lys Gln Pro Gln Gly Ser Arg
325 330 335
Ala Gln Ser Arg Leu Leu Lys Ser Lys Lys Gly Pro Ser Thr Ser Arg
340 345 350
His Lys Lys Leu Met Phe Asn Arg Asp Gly Pro Asp Ser Asp
355 360 365
<210> 42
<211> 1143
<212> DNA
<213> Loxodonta africana
<400> 42
acggagcagc cccagtcgga tctcagcact gagctccctc tgagtcaaga gacgttttca 60
tacttgggga aactcattcc tgagaagctg gttttgtccc cctcgttacg cccagcagta 120
gaggttgtag acgatctgct actcccagaa gatgctgcac actggctaga atgccatgtt 180
ggggttcaaa gaatatcagc agcctctgca ccagccaccc ccacacaagc cacctcctgg 240
actctgtcat cctctgtccc ttctcagaag acctacccca gcacctatgg tttctgtctg 300
ggcttcttgc attctgggac agtcaagtcc gtcacctaca cgtactcccc tgaacataac 360
atggtgtttt gccagcaggc aaagacctgt ccagtgcagc cgtgggtcac ctcaccaccc 420
ctgcccagca cctgtgttca caccatggcc atctaccaga cgtcagcata tgatggaggt 480
tgtgaagcaa tgcccccacc ttgagtgccg ctctgactat agcgattgcc tcgcccctcc 540
tcagcatctc atctaggtgg ggggaaaccc gcatgctgag tatttggagg acaccatcac 600
tctatgacat agtgtggggt gccctatgag ccaccagagg tcggttctga ctaccactat 660
ccacttcaac ttcatgtgta acagctcctg cactgggggc acgaacccat cctcaccatc 720
atcacactgg aagactccaa tggtaatctg ctggcacaca acagtttcga ggtgcgtatt 780
tgtacctgtc ctgggaaaga cagatgtaca gaggaagacg atttccacag gaaatgggag 840
ccttgacctg acccatcctc tgagaggatc actaagtgag cactgcccac cagcaccagc 900
tcaactacta agccaaagaa gccgccactg gatgaaaaat atttcaccct tcagatccgt 960
gggcatgaat gcttcaagat gttcctagag ctgaatgagg ccttggagct aaggatgccc 1020
aggctgggaa gcagccagag gggaaaaggg ctcaatccag ccttcccaag tctaagaaaa 1080
ggcaatttac ctcccgccac agaagactaa tgttcaagag agagcagcct gacttagact 1140
gat 1143
<210> 43
<211> 363
<212> PRT
<213> Loxodonta africana
<400> 43
Gly Ala Ala Pro Val Gly Ser Gln His Ala Pro Ser Glu Ser Arg Asp
1 5 10 15
Val Phe Ile Leu Gly Glu Thr His Ser Glu Ala Gly Phe Val Pro Leu
20 25 30
Val Thr Pro Ser Ser Arg Gly Cys Arg Arg Ser Ala Thr Pro Arg Arg
35 40 45
Cys Cys Thr Leu Ala Arg Met Pro Cys Trp Gly Ser Lys Asn Ile Ser
50 55 60
Ser Leu Cys Thr Ser His Pro His Thr Ser His Leu Leu Asp Ser Val
65 70 75 80
Ile Leu Cys Pro Phe Ser Glu Asp Leu Pro Gln His Leu Trp Phe Leu
85 90 95
Ser Gly Leu Leu Ala Phe Trp Asp Ser Gln Val Arg His Leu His Val
100 105 110
Leu Pro Thr His Gly Val Leu Pro Ala Gly Lys Asp Leu Ser Ser Ala
115 120 125
Ala Val Gly His Leu Thr Thr Pro Ala Gln His Leu Cys Ser His His
130 135 140
Gly His Leu Pro Asp Val Ser Ile Trp Arg Leu Ser Asn Ala Pro Thr
145 150 155 160
Leu Ser Ala Ala Leu Thr Ile Ala Ile Ala Ser Pro Leu Leu Ser Ile
165 170 175
Ser Ser Arg Trp Gly Glu Thr Arg Met Leu Ser Ile Trp Arg Thr Pro
180 185 190
Ser Leu Tyr Asp Ile Val Trp Gly Ala Leu Ala Thr Arg Gly Arg Phe
195 200 205
Leu Pro Leu Ser Thr Ser Thr Ser Cys Val Thr Ala Pro Ala Leu Gly
210 215 220
Ala Arg Thr His Pro His His His His Thr Gly Arg Leu Gln Trp Ser
225 230 235 240
Ala Gly Thr Gln Gln Phe Arg Gly Ala Tyr Leu Tyr Leu Ser Trp Glu
245 250 255
Arg Gln Met Tyr Arg Gly Arg Arg Phe Pro Gln Glu Met Gly Ala Leu
260 265 270
Thr Pro Ile Leu Glu Asp His Val Ser Thr Ala His Gln His Gln Leu
275 280 285
Asn Tyr Ala Lys Glu Ala Ala Thr Gly Lys Ile Phe His Pro Ser Asp
290 295 300
Pro Trp Ala Met Leu Gln Asp Val Pro Arg Ala Glu Gly Leu Gly Ala
305 310 315 320
Lys Asp Ala Gln Ala Gly Lys Gln Pro Glu Gly Lys Arg Ala Gln Ser
325 330 335
Ser Leu Pro Lys Ser Lys Lys Arg Gln Phe Thr Ser Arg His Arg Arg
340 345 350
Leu Met Phe Lys Arg Glu Gln Pro Asp Leu Asp
355 360
<210> 44
<211> 1130
<212> DNA
<213> Loxodonta africana
<400> 44
atggaggagc ccgagtcaga tctcagtact gagctccctc tgagtcaaga gacttttttg 60
tacttgggga aactccttcc tgagaagctg gttctgtccc cctcactgtc cccagcagcg 120
gaggcaggag acgatctgct actcccagaa gatgctgcag actggctaga aagccaagct 180
ggggctcaag aaacatcagc agcccctgca ccagccaccc ttataccagc ctcctcctgg 240
acactctcgt cctctgtccc ttcccagaag acctactgca gcaactgtgg tttccgtctt 300
ggcttcctgc attctgggac agccaagtct gtcacctgca tgtactcccc tgaccttaac 360
aagctgtttt gccagctggc aaagacctgt ccagtgcagc cgtagctcag ctcaccaccc 420
caccccagca cctgtgttca caccatggcc atctaccaga cgtcagcata tgacagaggt 480
catgcagcac tgcccccacc ttgagtgctg ctctgactat agcgacggcc tggccgctcc 540
tcagcatctt atccaggtgg gagaaatcct gtgtgctgat atttgtagga caccatcact 600
ctttgacata gtgtggggta ccctatgagc tacctcaggt cggctctgac taccaccatc 660
cacttcaact tcatgtgtag cagctcctgc aaggggggga ggaacccatc ctcaccatca 720
tcacactgga agactccagt ggtaatctgc taggacacaa cagtttcgaa gtgcatattt 780
gtacctgttc tgggagagac agacgtacag aggaagaaaa tttccacaac aagtgggagc 840
caccctctga gaggatcact aagtaagcac tgccaccagc actagctccc ctaccgagcc 900
aaagaagaag ccagtggatg aaaaatattt cacccttcag atccatgggc atgaatgatt 960
caagatattc ctagagttga atgaggcact ggagctgaag gatgcccagg ctgggaagca 1020
gccagagggg agcagggctc aatgcagcct tccaaactct aagaaagggg aatctaccac 1080
ccactgtaaa aaactaatgt tcaagagaga ggggcctgac tcagactgac 1130
<210> 45
<211> 361
<212> PRT
<213> Loxodonta africana
<400> 45
Met Glu Glu Pro Glu Ser Asp Leu Ser Thr Glu Leu Pro Leu Ser Gln
1 5 10 15
Glu Thr Phe Leu Tyr Leu Gly Lys Leu Leu Pro Glu Lys Leu Val Leu
20 25 30
Ser Pro Ser Leu Ser Pro Ala Ala Glu Ala Gly Asp Asp Leu Leu Leu
35 40 45
Pro Glu Asp Ala Ala Asp Trp Leu Glu Ser Gln Ala Gly Ala Gln Glu
50 55 60
Thr Ser Ala Ala Pro Ala Pro Ala Thr Leu Ile Pro Ala Ser Ser Trp
65 70 75 80
Thr Leu Ser Ser Ser Val Pro Ser Gln Lys Thr Tyr Cys Ser Asn Cys
85 90 95
Gly Phe Arg Leu Gly Phe Leu His Ser Gly Thr Ala Lys Ser Val Thr
100 105 110
Cys Met Tyr Ser Pro Asp Leu Asn Lys Leu Phe Cys Gln Leu Ala Lys
115 120 125
Thr Cys Pro Val Gln Pro Leu Ser Ser Pro Pro His Pro Ser Thr Cys
130 135 140
Val His Thr Met Ala Ile Tyr Gln Thr Ser Ala Tyr Asp Arg Gly His
145 150 155 160
Ala Ala Leu Pro Pro Pro Val Leu Leu Leu Arg Arg Pro Gly Arg Ser
165 170 175
Ser Ala Ser Tyr Pro Gly Gly Arg Asn Pro Val Cys Tyr Leu Asp Thr
180 185 190
Ile Thr Leu His Ser Val Gly Tyr Pro Met Ser Tyr Leu Arg Ser Ala
195 200 205
Leu Thr Thr Thr Ile His Phe Asn Phe Met Cys Ser Ser Ser Cys Lys
210 215 220
Gly Gly Arg Asn Pro Ser Ser Pro Ser Ser His Trp Lys Thr Pro Val
225 230 235 240
Val Ile Cys Asp Thr Thr Val Ser Lys Cys Ile Phe Val Pro Val Leu
245 250 255
Gly Glu Thr Asp Val Gln Arg Lys Lys Ile Ser Thr Thr Ser Gly Ser
260 265 270
His Pro Leu Arg Gly Ser Leu Ser Lys His Cys His Gln His Leu Pro
275 280 285
Tyr Arg Ala Lys Glu Glu Ala Ser Gly Lys Ile Phe His Pro Ser Asp
290 295 300
Pro Trp Ala Met Ile Gln Asp Ile Pro Arg Val Glu Gly Thr Gly Ala
305 310 315 320
Glu Gly Cys Pro Gly Trp Glu Ala Ala Arg Gly Glu Gln Gly Ser Met
325 330 335
Gln Pro Ser Lys Leu Glu Arg Gly Ile Tyr His Pro Leu Lys Thr Asn
340 345 350
Val Gln Glu Arg Gly Ala Leu Arg Leu
355 360
<210> 46
<211> 1131
<212> DNA
<213> Loxodonta africana
<400> 46
aatggaggag cccaagtcag atctcagtac tgagctccct ctgagtcaag agactttttc 60
atgcttgggg aaactccttc ctgagaaggt ggttctgtcc ccctcactgt ccccagcagc 120
ggaggcagta gacgatctgc tactcccaga agatgctgca gactgcctag aaagccaagc 180
tggggctcaa ggaatatcag cagcccctgc accagccacc cttacaccag ccacctcctg 240
gacactctca tcctctgtcc cttcccagaa gacctactgc agcaactgtg gtttccgtct 300
tggcttcctg cattctggga cagccaagtc tgtcacctgc atgtactccc ctggccttaa 360
caagctgttt tgccagctgg caaagacctg tccagtgcag ccgtagctca cctcaccagc 420
ccaccccagc acctgtgttc acaccatggc catctaccag atgtcagcat atgacagagg 480
tcgtgcagca ctgcccccac cttgagtgct gctccgacta tagcgatggc ctggccgctc 540
ctcagcatct tatccaggtg ggaggaatcc tgcgtgctga tatttgtagg acaccatcac 600
tcttcgacat agtgtggggt atcctatgag ctacctcagg tcggttctga ctaccaccat 660
ccacttcaac ttcatgtgta gcagctcctg catggggcgg ggggaaccca tcctcaccat 720
catcacactg gaagactccg atggtaatct gctaggacac aacagtttcg aggtgcatat 780
ttgtactgtt ctgggagaga cagacgtaca gaggaagaaa atttccacaa caagtgggag 840
ccaccctctg agaggatcac taagtaagca ctgcccacca gcaccagctc ctctaccgag 900
ccaaagaaga agccagtgga tgaaaaatat ttcaccctta agatccgtgg gcatgaatgc 960
ttcaagatgt tcctagagtt gaatgaggca ttggagctga aggatgccca ggctgggaag 1020
cagccagaag ggagcagggc ccaatgcagc cttccaaact ctaagaaagg ggaatctacc 1080
acccactgta aaaaactaat gttcaagaga gaggggcctg actcagactg a 1131
<210> 47
<211> 367
<212> PRT
<213> Loxodonta africana
<400> 47
Met Glu Glu Pro Lys Ser Asp Leu Ser Thr Glu Leu Pro Leu Ser Gln
1 5 10 15
Glu Thr Phe Ser Cys Leu Gly Lys Leu Leu Pro Glu Lys Val Val Leu
20 25 30
Ser Pro Ser Leu Ser Pro Ala Ala Glu Ala Val Asp Asp Leu Leu Leu
35 40 45
Pro Glu Asp Ala Ala Asp Cys Leu Glu Ser Gln Ala Gly Ala Gln Gly
50 55 60
Ile Ser Ala Ala Pro Ala Pro Ala Thr Leu Thr Pro Ala Thr Ser Trp
65 70 75 80
Thr Leu Ser Ser Ser Val Pro Ser Gln Lys Thr Tyr Cys Ser Asn Cys
85 90 95
Gly Phe Arg Leu Gly Phe Leu His Ser Gly Thr Ala Lys Ser Val Thr
100 105 110
Cys Met Tyr Ser Pro Gly Leu Asn Lys Leu Phe Cys Gln Leu Ala Lys
115 120 125
Thr Cys Pro Val Gln Pro Leu Thr Ser Pro Ala His Pro Ser Thr Cys
130 135 140
Val His Thr Met Ala Ile Tyr Gln Met Ser Ala Tyr Asp Arg Gly Arg
145 150 155 160
Ala Ala Leu Pro Pro Pro Val Leu Leu Arg Leu Arg Trp Pro Gly Arg
165 170 175
Ser Ser Ala Ser Tyr Pro Gly Gly Arg Asn Pro Ala Cys Tyr Leu Asp
180 185 190
Thr Ile Thr Leu Arg His Ser Val Gly Tyr Pro Met Ser Tyr Leu Arg
195 200 205
Ser Val Leu Thr Thr Thr Ile His Phe Asn Phe Met Cys Ser Ser Ser
210 215 220
Cys Met Gly Arg Gly Glu Pro Ile Leu Thr Ile Ile Thr Leu Glu Asp
225 230 235 240
Ser Asp Gly Asn Leu Leu Gly His Asn Ser Phe Glu Val His Ile Cys
245 250 255
Thr Val Leu Gly Glu Thr Asp Val Gln Arg Lys Lys Ile Ser Thr Thr
260 265 270
Ser Gly Ser His Pro Leu Arg Gly Ser Leu Ser Lys His Cys Pro Pro
275 280 285
Ala Pro Ala Pro Leu Pro Ser Gln Arg Arg Ser Gln Trp Met Lys Asn
290 295 300
Ile Ser Pro Leu Arg Ser Val Gly Met Asn Ala Ser Arg Cys Ser Ser
305 310 315 320
Met Arg His Trp Ser Arg Met Pro Arg Leu Gly Ser Ser Gln Lys Gly
325 330 335
Ala Gly Pro Asn Ala Ala Phe Gln Thr Leu Arg Lys Gly Asn Leu Pro
340 345 350
Pro Thr Val Lys Asn Cys Ser Arg Glu Arg Gly Leu Thr Gln Thr
355 360 365
<210> 48
<211> 1128
<212> DNA
<213> Loxodonta africana
<400> 48
aatggaggag cctcagtcag atctcagcac tgagctccct ctgagtcaag agacgttttc 60
atacttgggg aaactccttc ctgagaagct ggttctgttc ccctcactgt ccccagcagc 120
agaggcaata gacgatctgc tactcccaga agatgctgca gactggctag aaagccaagc 180
tggggctcaa ggaatatcag aagcctctac actagccacc tcctggacgc tgtcatcctc 240
tgtcccttct cagaagacct acccagcacc tatcgtttct gtctgggctt cttgcattct 300
gggacagcca agttcgtcac ctacacgtac tcccctgaac ttaacatgct gttttgccag 360
ctggcaaagg cctgtccagt gcagctgtgg gtcacctcaa cacccccgcc cagcacctgt 420
gttcacacca tggccatcta ccagacgtca gcatatgatg gaggtcgtga agcattgccc 480
cccaccttga gtgccgctct aactatagcg attgcttgga ccctactcag cacctcatgc 540
agtgggagga aacctgcatg ctgagtattt ggaggacacc atcactctat gacatagtgt 600
ggggtgccct atgagccacc agaggtcggt tctgactacc accatccact tcaacttcat 660
gtgtaacagc tcctgcatgg ggcgcatgaa cccattctca ccattatgac aatggaagac 720
tccaatggta atccgctggg acacaacagt ttcgaggtgc atatttgtac ctgtcctggg 780
agacacagat gtacagagga agacaatttc cacaacaagt gggagccttg ccctgagcca 840
ccctctggga ggatcactac gcaaacactg cccaccagca ccagctcctc tacgaagcca 900
aagaagaagc cactggatga aaaatacttc acccttcaga tccatgggca tgaatgtttc 960
aagatgttcc taaagctcaa tgaggccttg gagctgaagg atgcccaggc cgggaaacag 1020
ccagagggga gcagggctca atctagcctt cccaagtcta agaaaaggca atctacctcc 1080
cgccataaaa aactaatgtt caagagagag cagcctgact cagactga 1128
<210> 49
<211> 367
<212> PRT
<213> Loxodonta africana
<400> 49
Met Glu Glu Pro Gln Ser Asp Leu Ser Thr Glu Leu Pro Leu Ser Gln
1 5 10 15
Glu Thr Phe Ser Tyr Leu Gly Lys Leu Leu Pro Glu Lys Leu Val Leu
20 25 30
Phe Pro Ser Leu Ser Pro Ala Ala Glu Ala Ile Asp Asp Leu Leu Leu
35 40 45
Pro Glu Asp Ala Ala Asp Trp Leu Glu Ser Gln Ala Gly Ala Gln Gly
50 55 60
Ile Ser Glu Ala Ser Thr Leu Ala Thr Ser Trp Thr Leu Ser Ser Ser
65 70 75 80
Val Pro Ser Gln Lys Thr Tyr Pro Ala Pro Ile Val Ser Val Trp Ala
85 90 95
Ser Cys Ile Leu Gly Gln Pro Ser Ser Ser Pro Thr Arg Thr Pro Leu
100 105 110
Asn Leu Thr Cys Cys Phe Ala Ser Trp Gln Arg Pro Val Gln Cys Ser
115 120 125
Cys Gly Ser Pro Gln His Pro Arg Pro Ala Pro Val Phe Thr Pro Trp
130 135 140
Pro Ser Thr Arg Arg Gln His Met Met Glu Val Val Lys His Cys Pro
145 150 155 160
Pro Pro Val Pro Leu Leu Arg Leu Leu Gly Pro Tyr Ser Ala Pro His
165 170 175
Ala Val Gly Gly Asn Leu His Ala Glu Tyr Leu Glu Asp Thr Ile Thr
180 185 190
Leu His Ser Val Gly Cys Pro Met Ser His Gln Arg Ser Val Leu Thr
195 200 205
Thr Thr Ile His Phe Asn Phe Met Cys Asn Ser Ser Cys Met Gly Arg
210 215 220
Met Asn Pro Phe Ser Pro Leu Gln Trp Lys Thr Pro Met Val Ile Arg
225 230 235 240
Trp Asp Thr Thr Val Ser Arg Cys Ile Phe Val Pro Val Leu Gly Asp
245 250 255
Thr Asp Val Gln Arg Lys Thr Ile Ser Thr Thr Ser Gly Ser Leu Ala
260 265 270
Leu Ser His Pro Leu Gly Gly Ser Leu Arg Lys His Cys Pro Pro Ala
275 280 285
Pro Ala Pro Leu Arg Ser Gln Arg Arg Ser His Trp Met Lys Asn Thr
290 295 300
Ser Pro Phe Arg Ser Met Gly Met Asn Val Ser Arg Cys Ser Ser Ser
305 310 315 320
Met Arg Pro Trp Ser Arg Met Pro Arg Pro Gly Asn Ser Gln Arg Gly
325 330 335
Ala Gly Leu Asn Leu Ala Phe Pro Ser Leu Arg Lys Gly Asn Leu Pro
340 345 350
Pro Ala Ile Lys Asn Cys Ser Arg Glu Ser Ser Leu Thr Gln Thr
355 360 365
<210> 50
<211> 1121
<212> DNA
<213> Loxodonta africana
<400> 50
aatggaggag cctcagtcag atctcagcac tgagctccct ctgagtcaag ggacgttttc 60
atacttgggg aaactccttc ctgagaagct ggttctgtcc ccctcattgt ccccagcagc 120
ggaggcagta gatgatctgc tactctcaga agatgctgca gactggctag aaagccaagc 180
tggggctcaa ggaatatcag aagcgcctac actagccacc tcctggacgc tgtcatcctc 240
tgttccttct cagaagacct acccagcacc tatcatttct gtctgggctt cttgcattct 300
gggacagcca agtccgtcac ctacacgtac tcccctgaac ttaacatgct gttttgccag 360
ctggcaaagg cctgtccagt gcagccgtgg gtcacctcaa aacccccgtc cagcacctgt 420
gttcacacca tggccatcta ctagacgtca gcatatgatg gaggtcgtga agcactgccc 480
ccaccttgag tgccgctgtg actatagcga ttgcttggac cctcctcagc acctcatgca 540
gtgggaggaa acctgcatgc tgagtatttg gaggacacta tcactctatg acatagtgtg 600
gggtgcccta tgagccacca gaggtcagtt ctgactacca ccatccactt catgtgtaac 660
agctcctgca tggggggcag gaacccatcc tcaccatcat cacactggaa gactccaatg 720
gtaatccgct gggacacaac agtttcgagg tgcatatttg tacctgtcct gggagacgca 780
gatgtacaga ggaagacaat ttccacaaga agtgggagcc ttgccctgag ccaccctctg 840
ggaggatcac taagcaaaca ctgcccacca gcaccagctc ctctaccaag ccaaagaaga 900
agccactgga tgaaaaatac ttcacccttc agatccatgg gcatgaatgt ttcaagatgt 960
tcctaaagct caacgagacc ttggagctga aggatgccca ggctgggaag caaccagagg 1020
ggagcagggc tcaatgcagc cttcccaagt ctaagaaaag gcaatctatc tcccgccata 1080
aaaaaataat gttcaagaga gagcagcctg actcagactg a 1121
<210> 51
<211> 363
<212> PRT
<213> Loxodonta africana
<400> 51
Met Glu Glu Pro Gln Ser Asp Leu Ser Thr Glu Leu Pro Leu Ser Gln
1 5 10 15
Gly Thr Phe Ser Tyr Leu Gly Lys Leu Leu Pro Glu Lys Leu Val Leu
20 25 30
Ser Pro Ser Leu Ser Pro Ala Ala Glu Ala Val Asp Asp Leu Leu Leu
35 40 45
Ser Glu Asp Ala Ala Asp Trp Leu Glu Ser Gln Ala Gly Ala Gln Gly
50 55 60
Ile Ser Glu Ala Pro Thr Leu Ala Thr Ser Trp Thr Leu Ser Ser Ser
65 70 75 80
Val Pro Ser Gln Lys Thr Tyr Pro Ala Pro Ile Ile Ser Val Trp Ala
85 90 95
Ser Cys Ile Leu Gly Gln Pro Ser Pro Ser Pro Thr Arg Thr Pro Leu
100 105 110
Asn Leu Thr Cys Cys Phe Ala Ser Trp Gln Arg Pro Val Gln Cys Ser
115 120 125
Arg Gly Ser Pro Gln Asn Pro Arg Pro Ala Pro Val Phe Thr Pro Trp
130 135 140
Pro Ser Thr Arg Arg Gln His Met Met Glu Val Val Lys His Cys Pro
145 150 155 160
His Leu Glu Cys Arg Cys Asp Tyr Ser Asp Cys Leu Asp Pro Pro Gln
165 170 175
His Leu Met Gln Trp Glu Glu Thr Cys Met Leu Ser Ile Trp Arg Thr
180 185 190
Leu Ser Leu Tyr Asp Ile Val Trp Gly Ala Leu Ala Thr Arg Gly Gln
195 200 205
Phe Leu Pro Pro Ser Thr Ser Cys Val Thr Ala Pro Ala Trp Gly Ala
210 215 220
Gly Thr His Pro His His His His Thr Gly Arg Leu Gln Trp Ser Ala
225 230 235 240
Gly Thr Gln Gln Phe Arg Gly Ala Tyr Leu Tyr Leu Ser Trp Glu Thr
245 250 255
Gln Met Tyr Arg Gly Arg Gln Phe Pro Gln Glu Val Gly Ala Leu Pro
260 265 270
Ala Thr Leu Trp Glu Asp His Ala Asn Thr Ala His Gln His Gln Leu
275 280 285
Leu Tyr Gln Ala Lys Glu Glu Ala Thr Gly Lys Ile Leu His Pro Ser
290 295 300
Asp Pro Trp Ala Met Phe Gln Asp Val Pro Lys Ala Gln Arg Asp Leu
305 310 315 320
Gly Ala Glu Gly Cys Pro Gly Trp Glu Ala Thr Arg Gly Glu Gln Gly
325 330 335
Ser Met Gln Pro Ser Gln Val Glu Lys Ala Ile Tyr Leu Pro Pro Lys
340 345 350
Asn Asn Val Gln Glu Arg Ala Ala Leu Arg Leu
355 360
<210> 52
<211> 1129
<212> DNA
<213> Loxodonta africana
<400> 52
aatggaggag cctcagtcag atctcagcac tgagctccct ctgagtcaag agacgttttc 60
atacttgggg aaactccttc ctgagaagct ggttctgtcc ccctcactgt ccccagaagc 120
ggaggcagta gacaatctgc tactcccaga agatgctgca gactggctag aaagccaagc 180
tggggctcaa ggaatatcag aagcccctac actagccacc tcctggatgc tgtcatcctc 240
tgtcccttct cagaagacct gcccagcacc tatcgtttct gtctgggctt cttgcattct 300
gggacagcca agtccgtcac ctacacatac tcccctgaac ttaacatgct gttttgccag 360
ctggcaaagg cctgcccagt gcagctgtgg gtcacctcaa cacccccgcc cagcacctgt 420
gttcacacca tggccatcta ccagacgtca gcatatgatg gaggtcatga agcactgccg 480
ccaccttgag tgccgctctg actatagcaa ttgcttggac cctcctcagc acctcatcca 540
gtgggaggaa acctgcatgc tgagtatttg gaggacacca tcactctatg acatagtgtg 600
gggtgcccta gtagccacca gaggtcggtt ctgactacca ccatccactt caacttcatg 660
tgtaacagct cctgcatggg gggcaggaac ctatcctcac catcatcaca ctggaagact 720
ccaacggtaa tccgctggga cacaacagtt tcgaggtgca tatttgtacc tgtcctggga 780
gacacagatg tacagaggaa gacagtttcc acaagaagtg ggagccttgc cctgagccag 840
cctctgggag gatcactaag cgaacactgc ccaccagcac cagctcctct accaagccaa 900
agaagaagcc actggataaa aaatacttca cccttcagat ccatgggcat gaatgattca 960
agatgttcct aaagctcaac gaggccttgg agctgaagga tgcccaggct gggaggcagc 1020
cagaggggag cagggctcaa cccagccttc ccaagtctaa gaaaaggcaa tctacctcct 1080
gccataaaaa aaactaatgt tctagagaga gcagcctgac tcagactga 1129
<210> 53
<211> 366
<212> PRT
<213> Loxodonta africana
<400> 53
Met Glu Glu Pro Gln Ser Asp Leu Ser Thr Glu Leu Pro Leu Ser Gln
1 5 10 15
Glu Thr Phe Ser Tyr Leu Gly Lys Leu Leu Pro Glu Lys Leu Val Leu
20 25 30
Ser Pro Ser Leu Ser Pro Glu Ala Glu Ala Val Asp Asn Leu Leu Leu
35 40 45
Pro Glu Asp Ala Ala Asp Trp Leu Glu Ser Gln Ala Gly Ala Gln Gly
50 55 60
Ile Ser Glu Ala Pro Thr Leu Ala Thr Ser Trp Met Leu Ser Ser Ser
65 70 75 80
Val Pro Ser Gln Lys Thr Cys Pro Ala Pro Ile Val Ser Val Trp Ala
85 90 95
Ser Cys Ile Leu Gly Gln Pro Ser Pro Ser Pro Thr His Thr Pro Leu
100 105 110
Asn Leu Thr Cys Cys Phe Ala Ser Trp Gln Arg Pro Ala Gln Cys Ser
115 120 125
Cys Gly Ser Pro Gln His Pro Arg Pro Ala Pro Val Phe Thr Pro Trp
130 135 140
Pro Ser Thr Arg Arg Gln His Met Met Glu Val Met Lys His Cys Arg
145 150 155 160
His Leu Glu Cys Arg Ser Asp Tyr Ser Asn Cys Leu Asp Pro Pro Gln
165 170 175
His Leu Ile Gln Trp Glu Glu Thr Cys Met Leu Ser Ile Trp Arg Thr
180 185 190
Pro Ser Leu Tyr Asp Ile Val Trp Gly Ala Leu Val Ala Thr Arg Gly
195 200 205
Arg Phe Leu Pro Pro Ser Thr Ser Thr Ser Cys Val Thr Ala Pro Ala
210 215 220
Trp Gly Ala Gly Thr Tyr Pro His His His His Thr Gly Arg Leu Gln
225 230 235 240
Arg Ser Ala Gly Thr Gln Gln Phe Arg Gly Ala Tyr Leu Tyr Leu Ser
245 250 255
Trp Glu Thr Gln Met Tyr Arg Gly Arg Gln Phe Pro Gln Glu Val Gly
260 265 270
Ala Leu Pro Ala Ser Leu Trp Glu Asp His Ala Asn Thr Ala His Gln
275 280 285
His Gln Leu Leu Tyr Gln Ala Lys Glu Glu Ala Thr Gly Lys Ile Leu
290 295 300
His Pro Ser Asp Pro Trp Ala Met Ile Gln Asp Val Pro Lys Ala Gln
305 310 315 320
Arg Gly Leu Gly Ala Glu Gly Cys Pro Gly Trp Glu Ala Ala Arg Gly
325 330 335
Glu Gln Gly Ser Thr Gln Pro Ser Gln Val Glu Lys Ala Ile Tyr Leu
340 345 350
Leu Pro Lys Lys Leu Met Phe Arg Glu Gln Pro Asp Ser Asp
355 360 365
<210> 54
<211> 1127
<212> DNA
<213> Loxodonta africana
<400> 54
atggaggagc ctcagtcaga tctcagcact gagctccctt tgagtcaagg gacgttttca 60
tacttgggga aactccttcc tgagaagctg gttctgtccc tctcactgtc cccagcagca 120
gaggcagtag acgatctgtt actcccagaa gatgctgcag actggctaga aagccaagct 180
ggggctcaag gagtatcaga agcccctaca ctagccacct cctggacgtt gtcatcctct 240
gtcccttctc agaagaccta cccagcacct atcgtttctg tctgggcttc ttgcattctg 300
ggacagccaa gtccgtcacc tacacgtact cccctgaact taacatgctg ttttgccagc 360
tggcaaaggc ctgtccagtg cagccgtggg tcacctcaac aaccccgccc agcacctgtg 420
ttcacaccat ggccatctac cagacgtcag catatgatgg aggtcacgaa gcactgccgc 480
caccttgagt gccgctgtga ctatagcgat tgcttggacc ctcctcagca cctcatgcag 540
tgggaggaaa cctgcatgct gagtatttgg aggacaccat cactctatga catagtgtgg 600
ggtgccctag gagccaccag aggtcggttc tgactaccac catccacttc aacttcatgt 660
gtaacagctc ctgcatgggg ggcaggaacc catcctcacc atcatcacac tggaagactc 720
caatggtaat ccgctgggac acaacagttt cgaggtgcat atttgtactt gtcctgggag 780
acacagatgt acagaggaag acaatttcca taagaagtgg gagccttgcc ctgagccagg 840
ctcggggagg ttcactaagc gaacactgcc caccagcacc agctcctcta ccaagccaaa 900
gaagaagcca ctggatgaaa aatacttcac tcttcagatc catggccatg aatgtttcaa 960
gatgttccta aagctcaacg aggccttgga gctgaaggat gcccaggctg ggaagcagcc 1020
agaggggagc agggctcaat ccagacttcc caagtctaag aaaaggcaat ctacctcccg 1080
ccataaaaaa ctaatgttca agagagagca gcctgactca gactgac 1127
<210> 55
<211> 365
<212> PRT
<213> Loxodonta africana
<400> 55
Met Glu Glu Pro Gln Ser Asp Leu Ser Thr Glu Leu Pro Leu Ser Gln
1 5 10 15
Gly Thr Phe Ser Tyr Leu Gly Lys Leu Leu Pro Glu Lys Leu Val Leu
20 25 30
Ser Leu Ser Leu Ser Pro Ala Ala Glu Ala Val Asp Asp Leu Leu Leu
35 40 45
Pro Glu Asp Ala Ala Asp Trp Leu Glu Ser Gln Ala Gly Ala Gln Gly
50 55 60
Val Ser Glu Ala Pro Thr Leu Ala Thr Ser Trp Thr Leu Ser Ser Ser
65 70 75 80
Val Pro Ser Gln Lys Thr Tyr Pro Ala Pro Ile Val Ser Val Trp Ala
85 90 95
Ser Cys Ile Leu Gly Gln Pro Ser Pro Ser Pro Thr Arg Thr Pro Leu
100 105 110
Asn Leu Thr Cys Cys Phe Ala Ser Trp Gln Arg Pro Val Gln Cys Ser
115 120 125
Arg Gly Ser Pro Gln Gln Pro Arg Pro Ala Pro Val Phe Thr Pro Trp
130 135 140
Pro Ser Thr Arg Arg Gln His Met Met Glu Val Thr Lys His Cys Arg
145 150 155 160
His Leu Glu Cys Arg Cys Asp Tyr Ser Asp Cys Leu Asp Pro Pro Gln
165 170 175
His Leu Met Gln Trp Glu Glu Thr Cys Met Leu Ser Ile Trp Arg Thr
180 185 190
Pro Ser Leu Tyr Asp Ile Val Trp Gly Ala Leu Gly Ala Thr Arg Gly
195 200 205
Arg Phe Leu Pro Pro Ser Thr Ser Thr Ser Cys Val Thr Ala Pro Ala
210 215 220
Trp Gly Ala Gly Thr His Pro His His His His Thr Gly Arg Leu Gln
225 230 235 240
Trp Ser Ala Gly Thr Gln Gln Phe Arg Gly Ala Tyr Leu Tyr Leu Ser
245 250 255
Trp Glu Thr Gln Met Tyr Arg Gly Arg Gln Phe Pro Glu Val Gly Ala
260 265 270
Leu Pro Ala Arg Leu Gly Glu Val His Ala Asn Thr Ala His Gln His
275 280 285
Gln Leu Leu Tyr Gln Ala Lys Glu Glu Ala Thr Gly Lys Ile Leu His
290 295 300
Ser Ser Asp Pro Trp Pro Met Phe Gln Asp Val Pro Lys Ala Gln Arg
305 310 315 320
Gly Leu Gly Ala Glu Gly Cys Pro Gly Trp Glu Ala Ala Arg Gly Glu
325 330 335
Gln Gly Ser Ile Gln Thr Ser Gln Val Glu Lys Ala Ile Tyr Leu Pro
340 345 350
Pro Lys Thr Asn Val Gln Glu Arg Ala Ala Leu Arg Leu
355 360 365
<210> 56
<211> 1126
<212> DNA
<213> Loxodonta africana
<400> 56
agtggaggag cctcagtcag atctcagcac tgagctccct ctgagtcaag ggatgttttc 60
atacttgggg aaactccttc ctgagaagct ggttctgtcc ctctcactgt ccccagcagc 120
agaggcagta gacgatctgc tactcccaga agatgctgca gactggctag aaagccaagc 180
tggggctcaa ggaatatcag aagcccctac gctagccacc tcctggacgc tgtcatcctc 240
tgtcccttct cagaagacct acccagcacc tatcacttct gtctgggctt cttgcattct 300
gggacagcca agtctgtcac ctacacgtac tcccctgaac ttaacgtgct gttttgccag 360
ctggcaaagg cctgtccagt gcagctgtgg gtcacctcaa catccctgcc cagcacctgt 420
gttcacacca tggccatcta ccagacgtca gcatatgatg gaggtcgtga agcactgccc 480
ccaccttgag tgccgctctg actatagcga ttgcttagac cctcctcagc accttatcca 540
gtgggaggaa acctgcatgc tgagtatttg gaggacacca tcactctatg acatagcgtg 600
gggtgcccta tgagccacca gaggtcggtt ctgactacca ccatccactt caacttcatg 660
tgtaacagct cctgcatggg gggcaggaac ccatcctcac catcatcaca ctggaagact 720
ccaatggtaa tccgctggga cacaacagtt tcgaggtgca tatttgtact tgtcctggga 780
gacacagatg tacagaggaa gacaatttcc ataagaagtg ggagccttgc cctgagccag 840
gctcggggag gatcactaag gaacactgcc caccagcacc agctcctcta ccaagccaaa 900
gaagaagcca ctggatgaaa aatacttcac tcttcagatc catggccatg aatgcttcaa 960
gatgttccta aagctcaatg aggccttgga gctcaaggat gcccaggctg ggaagcagcc 1020
agaggggaac agggctcaat ccagccttcc caagtctaag aaaaggcaat ctacctcccg 1080
ccataaaaaa cttatgttca agagagagca gcctgactca gactga 1126
<210> 57
<211> 368
<212> PRT
<213> Loxodonta africana
<400> 57
Val Glu Glu Pro Gln Ser Asp Leu Ser Thr Glu Leu Pro Leu Ser Gln
1 5 10 15
Gly Met Phe Ser Tyr Leu Gly Lys Leu Leu Pro Glu Lys Leu Val Leu
20 25 30
Ser Leu Ser Leu Ser Pro Ala Ala Glu Ala Val Asp Asp Leu Leu Leu
35 40 45
Pro Glu Asp Ala Ala Asp Trp Leu Glu Ser Gln Ala Gly Ala Gln Gly
50 55 60
Ile Ser Glu Ala Pro Thr Leu Ala Thr Ser Trp Thr Leu Ser Ser Ser
65 70 75 80
Val Pro Ser Gln Lys Thr Tyr Pro Ala Pro Ile Thr Ser Val Trp Ala
85 90 95
Ser Cys Ile Leu Gly Gln Pro Ser Leu Ser Pro Thr Arg Thr Pro Leu
100 105 110
Asn Leu Thr Cys Cys Phe Ala Ser Trp Gln Arg Pro Val Gln Cys Ser
115 120 125
Cys Gly Ser Pro Gln His Pro Cys Pro Ala Pro Val Phe Thr Pro Trp
130 135 140
Pro Ser Thr Arg Arg Gln His Met Met Glu Val Val Lys His Cys Pro
145 150 155 160
His Leu Glu Cys Arg Ser Asp Tyr Ser Asp Cys Leu Asp Pro Pro Gln
165 170 175
His Leu Ile Gln Trp Glu Glu Thr Cys Met Leu Ser Ile Trp Arg Thr
180 185 190
Pro Ser Leu Tyr Asp Ile Ala Trp Gly Ala Leu Ala Thr Arg Gly Arg
195 200 205
Phe Leu Pro Pro Ser Thr Ser Thr Ser Cys Val Thr Ala Pro Ala Trp
210 215 220
Gly Ala Gly Thr His Pro His His His His Thr Gly Arg Leu Gln Trp
225 230 235 240
Ser Ala Gly Thr Gln Gln Phe Arg Gly Ala Tyr Leu Tyr Leu Ser Trp
245 250 255
Glu Thr Gln Met Tyr Arg Gly Arg Gln Phe Pro Glu Val Gly Ala Leu
260 265 270
Pro Ala Arg Leu Gly Glu Asp His Gly Thr Leu Pro Thr Ser Thr Ser
275 280 285
Ser Ser Thr Lys Pro Lys Lys Lys Pro Leu Asp Glu Lys Tyr Phe Thr
290 295 300
Leu Gln Ile His Gly His Glu Cys Phe Lys Met Phe Leu Lys Leu Asn
305 310 315 320
Glu Ala Leu Glu Leu Lys Asp Ala Gln Ala Gly Lys Gln Pro Glu Gly
325 330 335
Asn Arg Ala Gln Ser Ser Leu Pro Lys Ser Lys Lys Arg Gln Ser Thr
340 345 350
Ser Arg His Lys Lys Leu Met Phe Lys Arg Glu Gln Pro Asp Ser Asp
355 360 365
<210> 58
<211> 1135
<212> DNA
<213> Loxodonta africana
<400> 58
atggaggagc ccgagtcaga tctcagtact gagctccttc tgagtcaaga gactttttcg 60
tacttgggga aactccttcc tgagaagctg gttctgtccc cctcactgtc cccagcagcg 120
gaggcagtag acgatctgct actcccagaa gatgctgcag actggctaga aagccaagct 180
ggggctcaag gaatatcagc agcccctgca ccagccaccc ttacaccagc cacctcctag 240
acactttcat cctctgtccc ttcccagaag acctactgca gcaactgtgg tttccatctt 300
ggcttcctgc attctgggac agccaagtct gtcacctgca cgtactcccc tgaccttaac 360
aagctgttct gccagctggc aaagacctgt ccagtgcagc cgtagctcag ctcaccaccc 420
cactccaccc cagcacctgt gttcacacca tggccatcta ccagatgtca gcacatgaca 480
gaggtcgtgc agcactgccc ccatcttgag tgctactccg actatagcga tggcctggcc 540
gctcctcagc atcttatcca ggtgggagga atcctgcgtg ctgatatttg taggacacca 600
ttactcttcg acatagtgtg gggtacccta tgagctacct caggtcggtt ctgactacca 660
ccatccactt caacttcatg tgtagcagct cctgcatggg gggggggaac ccatcctcac 720
catcatcaca ctggaagact ccgatggtaa tctgctagga cacaacagtt tcgaggtgca 780
tatttgtact gttctgggag agacagacgt acagaggaag aaaatttcca caacaagtgg 840
gagccagcct ctgagaggat cactgagtaa gcactgccca ccagcaccag ctcctctacc 900
gagccaaaga agaagccagt ggacgaaaaa tatttcaccc ttaagatcca tgggcatgaa 960
tgcttcaaga tgttcctaga gttgaacgag gcattggagc tgaaggatgc ccaggctggg 1020
aagcagtcag aggggagcag ggatcaatgc agccttccaa actctaggaa aggggaatct 1080
accacccact gtaaaaaact aatgttcaag agagaggggc ctgactcaga ctgac 1135
<210> 59
<211> 371
<212> PRT
<213> Loxodonta africana
<400> 59
Met Glu Glu Pro Glu Ser Asp Leu Ser Thr Glu Leu Leu Leu Ser Gln
1 5 10 15
Glu Thr Phe Ser Tyr Leu Gly Lys Leu Leu Pro Glu Lys Leu Val Leu
20 25 30
Ser Pro Ser Leu Ser Pro Ala Ala Glu Ala Val Asp Asp Leu Leu Leu
35 40 45
Pro Glu Asp Ala Ala Asp Trp Leu Glu Ser Gln Ala Gly Ala Gln Gly
50 55 60
Ile Ser Ala Ala Pro Ala Pro Ala Thr Leu Thr Pro Ala Thr Ser Thr
65 70 75 80
Leu Ser Ser Ser Val Pro Ser Gln Lys Thr Tyr Cys Ser Asn Cys Gly
85 90 95
Phe His Leu Gly Phe Leu His Ser Gly Thr Ala Lys Ser Val Thr Cys
100 105 110
Thr Tyr Ser Pro Asp Leu Asn Lys Leu Phe Cys Gln Leu Ala Lys Thr
115 120 125
Cys Pro Val Gln Pro Leu Ser Ser Pro Pro His Ser Thr Pro Ala Pro
130 135 140
Val Phe Thr Pro Trp Pro Ser Thr Arg Cys Gln His Met Thr Glu Val
145 150 155 160
Val Gln His Cys Pro His Leu Glu Cys Tyr Ser Asp Tyr Ser Asp Gly
165 170 175
Leu Ala Ala Pro Gln His Leu Ile Gln Val Gly Gly Ile Leu Arg Ala
180 185 190
Asp Ile Cys Arg Thr Pro Leu Leu Phe Asp Ile Val Trp Gly Thr Leu
195 200 205
Ala Thr Ser Gly Arg Phe Leu Pro Pro Ser Thr Ser Thr Ser Cys Val
210 215 220
Ala Ala Pro Ala Trp Gly Gly Gly Thr His Pro His His His His Thr
225 230 235 240
Gly Arg Leu Arg Trp Ser Ala Arg Thr Gln Gln Phe Arg Gly Ala Tyr
245 250 255
Leu Tyr Cys Ser Gly Arg Asp Arg Arg Thr Glu Glu Glu Asn Phe His
260 265 270
Asn Lys Trp Glu Pro Ala Ser Glu Arg Ile Thr Glu Ala Leu Pro Thr
275 280 285
Ser Thr Ser Ser Ser Thr Glu Pro Lys Lys Lys Pro Val Asp Glu Lys
290 295 300
Tyr Phe Thr Leu Lys Ile His Gly His Glu Cys Phe Lys Met Phe Leu
305 310 315 320
Glu Leu Asn Glu Ala Leu Glu Leu Lys Asp Ala Gln Ala Gly Lys Gln
325 330 335
Ser Glu Gly Ser Arg Asp Gln Cys Ser Leu Pro Asn Ser Arg Lys Gly
340 345 350
Glu Ser Thr Thr His Cys Lys Lys Leu Met Phe Lys Arg Glu Gly Pro
355 360 365
Asp Ser Asp
370
<210> 60
<211> 1127
<212> DNA
<213> Loxodonta africana
<400> 60
agtggaggag cctcagtcag atctcagcac tgagctccct ctgagtcaag ggacgttttc 60
atacttgggg aaactccttc ctgagaagct ggttctgtcc ctctcactgt ccccagcagc 120
agaggcagta gacgatctgc tactcccaga agatgctgca gactggctag aaagccaagc 180
tggggctcaa ggaatatcag aagcccctac actagccacc tcctggacgc tgtcatcctc 240
tgtcccttct cagaagacct acccagcacc tatcgtttct gtctgggctt cttgcattct 300
gggacagcca agtctgtcac ctacacgtac tcccctgaac ttaacatgct gttttgccgg 360
ctggcaaagg cctgtccagt gcagctgtgg gtcacctcaa cacccccgcc cagcacctgt 420
gttcacacca tggccatcta ccagacgtca gcatatgatg gaggtcgtga agcactgccc 480
ccaccttgag tgccgctgtg actatagcga ttgcttggac cctcctcagc acctcatcca 540
gtaggaggaa acctgcatgc tgagtatttg gaggacacca tcactctatg acatagtgtg 600
gggtgcccta ggagccacca gaggtcggtt ctgactacca ccatccactt caacttcatg 660
tgtaacagct cctgcatggg gggcaggaac ccatcctcac catcatcact ctggaatact 720
ccaatggtaa tccgctggga cacaacagtt tcgaggtgca tatttgtacc tgtcctggga 780
gacacagatg tacagaggaa gacaatttcc agaagaagtg ggagccttgc cctgagccac 840
cctctgggag gatcactaag caaacactgc ccaccagcac cagctcctct atcaagccaa 900
agaagaagcc actggatgaa aaatacttca cccttcagat ccatgggcat gaatgtttca 960
agatgttcct aaagctcaac gaggccttgg agctgaagga tgcccaggct gggaagcaac 1020
caggggggag cagggctcaa tccagccttc ccaagtctaa gaaaaggcaa tctatctccc 1080
accataaaaa aataatgttc aagagagagc agcctgactc agactga 1127
<210> 61
<211> 365
<212> PRT
<213> Loxodonta africana
<400> 61
Val Glu Glu Pro Gln Ser Asp Leu Ser Thr Glu Leu Pro Leu Ser Gln
1 5 10 15
Gly Thr Phe Ser Tyr Leu Gly Lys Leu Leu Pro Glu Lys Leu Val Leu
20 25 30
Ser Leu Ser Leu Ser Pro Ala Ala Glu Ala Val Asp Asp Leu Leu Leu
35 40 45
Pro Glu Asp Ala Ala Asp Trp Leu Glu Ser Gln Ala Gly Ala Gln Gly
50 55 60
Ile Ser Glu Ala Pro Thr Leu Ala Thr Ser Trp Thr Leu Ser Ser Ser
65 70 75 80
Val Pro Ser Gln Lys Thr Tyr Pro Ala Pro Ile Val Ser Val Trp Ala
85 90 95
Ser Cys Ile Leu Gly Gln Pro Ser Leu Ser Pro Thr Arg Thr Pro Leu
100 105 110
Asn Leu Thr Cys Cys Phe Ala Gly Trp Gln Arg Pro Val Gln Cys Ser
115 120 125
Cys Gly Ser Pro Gln His Pro Arg Pro Ala Pro Val Phe Thr Pro Trp
130 135 140
Pro Ser Thr Arg Arg Gln His Met Met Glu Val Val Lys His Cys Pro
145 150 155 160
His Leu Glu Cys Arg Cys Asp Tyr Ser Asp Cys Leu Asp Pro Pro Gln
165 170 175
His Leu Ile Gln Glu Glu Thr Cys Met Leu Ser Ile Trp Arg Thr Pro
180 185 190
Ser Leu Tyr Asp Ile Val Trp Gly Ala Leu Gly Ala Thr Arg Gly Arg
195 200 205
Phe Leu Pro Pro Ser Thr Ser Thr Ser Cys Val Thr Ala Pro Ala Trp
210 215 220
Gly Ala Gly Thr His Pro His His His His Ser Gly Ile Leu Gln Trp
225 230 235 240
Ser Ala Gly Thr Gln Gln Phe Arg Gly Ala Tyr Leu Tyr Leu Ser Trp
245 250 255
Glu Thr Gln Met Tyr Arg Gly Arg Gln Phe Pro Glu Glu Val Gly Ala
260 265 270
Leu Pro Ala Thr Leu Trp Glu Asp His Ala Asn Thr Ala His Gln His
275 280 285
Gln Leu Leu Tyr Gln Ala Lys Glu Glu Ala Thr Gly Lys Ile Leu His
290 295 300
Pro Ser Asp Pro Trp Ala Met Phe Gln Asp Val Pro Lys Ala Gln Arg
305 310 315 320
Gly Leu Gly Ala Glu Gly Cys Pro Gly Trp Glu Ala Thr Arg Gly Glu
325 330 335
Gln Gly Ser Ile Gln Pro Ser Gln Val Glu Lys Ala Ile Tyr Leu Pro
340 345 350
Pro Lys Asn Asn Val Gln Glu Arg Ala Ala Leu Arg Leu
355 360 365
<210> 62
<211> 1126
<212> DNA
<213> Loxodonta africana
<400> 62
aatggaggag cctcagtcag atctcagcac tgagctccct ctgagtcaag ggacgttttc 60
atacttgggg aaactccttc ctgagaagct ggttctgtcc ctctcactgt ccccagcagc 120
agaggcagta gacgatctgt tactcccaga agatgctgca gactggctag aaagccaagc 180
tggggctcaa ggagtatcag aagcccctac actagccacc tcctggacgt tgtcatcctc 240
tgtcccttct cagaagacct acccagcacc tatcgtttct gtctgggctt cttgcattct 300
gggacagcca agtctgtcac ctacacgtac tccctgaact taacatgctg ttttgccggc 360
tggcaaaggc ctgtccagtg cagctgtggg tcacctcaac acccccgccc agcacctgtg 420
ttcacaccat ggccatctac cagacgtcag catatgatgg aggtcgtgaa gcactgcccc 480
caccttgagt gccgctgtga ctatagcgat tgcttggacc ctcctcagca cctcatgcag 540
tgggaggaaa cctgcatgct gagtatttgg aggacaccat cactctatga catagtgtgg 600
ggtgccctag gagccaccag aggtcggttc tgactaccac catccacttc aacttcatgt 660
gtaacagctc ctgcatgggg agcatgaacc catcctcacc atcatcacac tggaagactc 720
caatggtaat ctgctgggac acaacacttt tgaggtgcat atttgtacct gtcccgggag 780
acacagatgt acagaggaag acaatttcca caacaagtgg gagccttgcc ctgagccacc 840
ctctgggagg atcactaagc aaacactgcc caccagcacc agctcctcta ccaagccaaa 900
gaagaagcca ctggatgaaa aatacttcac tcttcagatc catggccatg aatgcttcaa 960
gatgttccta aagctcaacg aggccttgga gttgaaggat gcccaggctg ggaagcagcc 1020
agaggggaac agggctcaat ccagccttcc caagtctaag aaaaggcaat ctacctccca 1080
ccataaaaaa ctaacgttca agagagagca gcctgactca gactga 1126
<210> 63
<211> 366
<212> PRT
<213> Loxodonta africana
<400> 63
Met Glu Glu Pro Gln Ser Asp Leu Ser Thr Glu Leu Pro Leu Ser Gln
1 5 10 15
Gly Thr Phe Ser Tyr Leu Gly Lys Leu Leu Pro Glu Lys Leu Val Leu
20 25 30
Ser Leu Ser Leu Ser Pro Ala Ala Glu Ala Val Asp Asp Leu Leu Leu
35 40 45
Pro Glu Asp Ala Ala Asp Trp Leu Glu Ser Gln Ala Gly Ala Gln Gly
50 55 60
Val Ser Glu Ala Pro Thr Leu Ala Thr Ser Trp Thr Leu Ser Ser Ser
65 70 75 80
Val Pro Ser Gln Lys Thr Tyr Pro Ala Pro Ile Val Ser Val Trp Ala
85 90 95
Ser Cys Ile Leu Gly Gln Pro Ser Leu Ser Pro Thr Arg Thr Pro Thr
100 105 110
His Ala Val Leu Pro Ala Gly Lys Gly Leu Ser Ser Ala Ala Val Gly
115 120 125
His Leu Asn Thr Pro Ala Gln His Leu Cys Ser His His Gly His Leu
130 135 140
Pro Asp Val Ser Ile Trp Arg Ser Ser Thr Ala Pro Thr Leu Ser Ala
145 150 155 160
Ala Val Thr Ile Ala Ile Ala Trp Thr Leu Leu Ser Thr Ser Cys Ser
165 170 175
Gly Arg Lys Pro Ala Cys Val Phe Gly Gly His His His Ser Met Thr
180 185 190
Cys Gly Val Pro Glu Pro Pro Glu Val Gly Ser Asp Tyr His His Pro
195 200 205
Leu Gln Leu His Val Gln Leu Leu His Gly Glu His Glu Pro Ile Leu
210 215 220
Thr Ile Ile Thr Leu Glu Asp Ser Asn Gly Asn Leu Leu Gly His Asn
225 230 235 240
Thr Phe Glu Val His Ile Cys Thr Cys Pro Gly Arg His Arg Cys Thr
245 250 255
Glu Glu Asp Asn Phe His Asn Lys Trp Glu Pro Cys Pro Glu Pro Pro
260 265 270
Ser Gly Arg Ile Thr Lys Gln Thr Leu Pro Thr Ser Thr Ser Ser Ser
275 280 285
Thr Lys Pro Lys Lys Lys Pro Leu Asp Glu Lys Tyr Phe Thr Leu Gln
290 295 300
Ile His Gly His Glu Cys Phe Lys Met Phe Leu Lys Leu Asn Glu Ala
305 310 315 320
Leu Glu Leu Lys Asp Ala Gln Ala Gly Lys Gln Pro Glu Gly Asn Arg
325 330 335
Ala Gln Ser Ser Leu Pro Lys Ser Lys Lys Arg Gln Ser Thr Ser His
340 345 350
His Lys Lys Leu Thr Phe Lys Arg Glu Gln Pro Asp Ser Asp
355 360 365
<210> 64
<211> 1126
<212> DNA
<213> Loxodonta africana
<400> 64
atggaagagc ctcagtcaga tctcagcact gagctccctc tgagtcaagg gacgttttca 60
tacttgggga aactccttcc tgagaagctg gttctgtccc tctcactgtc cccagcagca 120
gaggcaatag acgatctact actcccagaa gatgctgcag actggctaga aagccaagct 180
ggggctcaag gagtatcaga agcccctaca ctagccacct cctggacgtt gtcatcctct 240
gtcccttctc agaagaccta cccagcacct atcgtttctg tctgggcttc ttgcattctg 300
ggacagccaa gtctgtcacc tacacgtact ccctgaactt aacatgctgt tttgccagct 360
ggcaaaggcc tgtccagtgc agctgtgggt cacctcaaca cccccgccaa gcacctgtgt 420
tcacaccatg gccatctacc agacgtcagc atatgatgga ggtcgtgaag cactgccccc 480
accttgagtg ccgctctgac tatagcgatt gcttggaccc tcctcagcac ctcatccagt 540
gggaggaaac ctgcatgctg agtatttgga ggacaccatc actctatgac atagcgtggg 600
gtgccctatg agccaccaga ggtcggttct gactaccacc atccacttca acctcatgtg 660
taacagctcc tgcatggggg gcaggaagcc atcctcacca tcatcacact ggaagactcc 720
aatggtaatc cgctgggaca caacagtttc gaggtgcata tttgtacttg tcctgggaga 780
cacagatgta cagaggaaga caatttccat aagaagtggg agccttgccc tgagccaggc 840
tcggggagga tcactaagcg aacactgccc accagcacca gctcctctat caagccaaag 900
aagaagccac tggatgaaaa atacttcact cttcagatcc atggccatga atgcttcaag 960
atgttcctaa agctcaacga ggccttggag ctgaaggatg cccaggctgg gaagcagcca 1020
gaggggagca gggctcaatc cagccttccc aagtctaaga aaaggcaatc tacctcccgc 1080
cataaaaaac ttatgttcaa gagagagcag cctgactcag actgat 1126
<210> 65
<211> 367
<212> PRT
<213> Loxodonta africana
<400> 65
Met Glu Glu Pro Gln Ser Asp Leu Ser Thr Glu Leu Pro Leu Ser Gln
1 5 10 15
Gly Thr Phe Ser Tyr Leu Gly Lys Leu Leu Pro Glu Lys Leu Val Leu
20 25 30
Ser Leu Ser Leu Ser Pro Ala Ala Glu Ala Ile Asp Asp Leu Leu Leu
35 40 45
Pro Glu Asp Ala Ala Asp Trp Leu Glu Ser Gln Ala Gly Ala Gln Gly
50 55 60
Val Ser Glu Ala Pro Thr Leu Ala Thr Ser Trp Thr Leu Ser Ser Ser
65 70 75 80
Val Pro Ser Gln Lys Thr Tyr Pro Ala Pro Ile Val Ser Val Trp Ala
85 90 95
Ser Cys Ile Leu Gly Gln Pro Ser Leu Ser Pro Thr Arg Thr Pro Thr
100 105 110
His Ala Val Leu Pro Ala Gly Lys Gly Leu Ser Ser Ala Ala Val Gly
115 120 125
His Leu Asn Thr Pro Ala Lys His Leu Cys Ser His His Gly His Leu
130 135 140
Pro Asp Val Ser Ile Trp Arg Ser Ser Thr Ala Pro Thr Leu Ser Ala
145 150 155 160
Ala Leu Thr Ile Ala Ile Ala Trp Thr Leu Leu Ser Thr Ser Ser Ser
165 170 175
Gly Arg Lys Pro Ala Cys Val Phe Gly Gly His His His Ser Met Thr
180 185 190
Arg Gly Val Pro Tyr Glu Pro Pro Glu Val Gly Ser Asp Tyr His His
195 200 205
Pro Leu Gln Pro His Val Gln Leu Leu His Gly Gly Gln Glu Ala Ile
210 215 220
Leu Thr Ile Ile Thr Leu Glu Asp Ser Asn Gly Asn Pro Leu Gly His
225 230 235 240
Asn Ser Phe Glu Val His Ile Cys Thr Cys Pro Gly Arg His Arg Cys
245 250 255
Thr Glu Glu Asp Asn Phe His Lys Lys Trp Glu Pro Cys Pro Glu Pro
260 265 270
Gly Ser Gly Arg Ile Thr Lys Arg Thr Leu Pro Thr Ser Thr Ser Ser
275 280 285
Ser Ile Lys Pro Lys Lys Lys Pro Leu Asp Glu Lys Tyr Phe Thr Leu
290 295 300
Gln Ile His Gly His Glu Cys Phe Lys Met Phe Leu Lys Leu Asn Glu
305 310 315 320
Ala Leu Glu Leu Lys Asp Ala Gln Ala Gly Lys Gln Pro Glu Gly Ser
325 330 335
Arg Ala Gln Ser Ser Leu Pro Lys Ser Lys Lys Arg Gln Ser Thr Ser
340 345 350
Arg His Lys Lys Leu Met Phe Lys Arg Glu Gln Pro Asp Ser Asp
355 360 365
<210> 66
<211> 1129
<212> DNA
<213> Loxodonta africana
<400> 66
aatggagaag cccaagtcag atctcagtac tgagctccct ctgagtcaag agactttttc 60
atacttgggg aaactccttc ctgagaagct ggttctgtcc ccctcactgt ccccagcagc 120
ggaggcagta gacgatctgc tgctcccagg agatgctgca gactgcctag aaagccaagc 180
tggggctcaa ggaatatcag cagcccctgc accagccacc ctgacaccag ccacctcctg 240
gacactctca ttctctgtcc cttcccagaa gacctactgc agtaactgtg gtttccgtct 300
tggcttcctg cattctggga cagccaagtc tgtcacctgc atgtactccc ctggccttaa 360
caagctgttt tgccagctgg caaagacctg tccagtgcag ccgtagctca gctcaccacc 420
ccaccccagc acctgtgttc acaccatggc catctaccag acgtcagcat atgacagagg 480
tcgtgcagca ctgcccccac cttgagtgct gctccgacta tagcgatggc ctggccgctc 540
ctcagcatct tatccaggtg ggaggaatcc tgcgtgctga tatttgtagg acaccatcac 600
tcttcgacat agtgtggggt accgtatgag ctacctcagg tcggttctga ctaccaccat 660
ccacttcaac ttcatgtgta gcagctcctg catggcgggg ggaacccatc ctcaccatca 720
tcacactgga agactccgat ggtaatctgc taggacacaa cagttttgag gtgcatattt 780
gtactgttct gggagagaca gacgtacaga ggaagaaaat ttccacaaca agtgggagcc 840
accctctgag aggatcacta agtaagcact gcacaccagc accagctcct ctaccgagcc 900
aaagaagaag ccagtggatg aaaaatattt cacccttaag atccgtgggc atgaatgctt 960
caagatgttc ctagagttga atgaggcatt ggagctgaag gatgcccagg ctgggaagca 1020
gccagagggg agcagggctc aatgcagcct tccaaactct aagaaagggg aatctaccac 1080
ccactgtaaa aaactaatgt tcaagagaga ggggcctgac tcagactga 1129
<210> 67
<211> 367
<212> PRT
<213> Loxodonta africana
<400> 67
Met Glu Lys Pro Lys Ser Asp Leu Ser Thr Glu Leu Pro Leu Ser Gln
1 5 10 15
Glu Thr Phe Ser Tyr Leu Gly Lys Leu Leu Pro Glu Lys Leu Val Leu
20 25 30
Ser Pro Ser Leu Ser Pro Ala Ala Glu Ala Val Asp Asp Leu Leu Leu
35 40 45
Pro Gly Asp Ala Ala Asp Cys Leu Glu Ser Gln Ala Gly Ala Gln Gly
50 55 60
Ile Ser Ala Ala Pro Ala Pro Ala Thr Leu Thr Pro Ala Thr Ser Trp
65 70 75 80
Thr Leu Ser Phe Ser Val Pro Ser Gln Lys Thr Tyr Cys Ser Asn Cys
85 90 95
Gly Phe Arg Leu Gly Phe Leu His Ser Gly Thr Ala Lys Ser Val Thr
100 105 110
Cys Met Tyr Ser Pro Gly Leu Asn Lys Leu Phe Cys Gln Leu Ala Lys
115 120 125
Thr Cys Pro Val Gln Pro Leu Ser Ser Pro Pro His Pro Ser Thr Cys
130 135 140
Val His Thr Met Ala Ile Tyr Gln Thr Ser Ala Tyr Asp Arg Gly Arg
145 150 155 160
Ala Ala Leu Pro Pro Pro Val Leu Leu Arg Leu Arg Trp Pro Gly Arg
165 170 175
Ser Ser Ala Ser Tyr Pro Gly Gly Arg Asn Pro Ala Cys Tyr Leu Asp
180 185 190
Thr Ile Thr Leu Arg His Ser Val Gly Tyr Arg Met Ser Tyr Leu Arg
195 200 205
Ser Val Leu Thr Thr Thr Ile His Phe Asn Phe Met Cys Ser Ser Ser
210 215 220
Cys Met Ala Gly Gly Thr His Pro His His His His Thr Gly Arg Leu
225 230 235 240
Arg Trp Ser Ala Arg Thr Gln Gln Phe Gly Ala Tyr Leu Tyr Cys Ser
245 250 255
Gly Arg Asp Arg Arg Thr Glu Glu Glu Asn Phe His Asn Lys Trp Glu
260 265 270
Pro Pro Ser Glu Arg Ile Thr Lys Ala Leu His Thr Ser Thr Ser Ser
275 280 285
Ser Thr Glu Pro Lys Lys Lys Pro Val Asp Glu Lys Tyr Phe Thr Leu
290 295 300
Lys Ile Arg Gly His Glu Cys Phe Lys Met Phe Leu Glu Leu Asn Glu
305 310 315 320
Ala Leu Glu Leu Lys Asp Ala Gln Ala Gly Lys Gln Pro Glu Gly Ser
325 330 335
Arg Ala Gln Cys Ser Leu Pro Asn Ser Lys Lys Gly Glu Ser Thr Thr
340 345 350
His Cys Lys Lys Leu Met Phe Lys Arg Glu Gly Pro Asp Ser Asp
355 360 365
<210> 68
<211> 1126
<212> DNA
<213> Loxodonta africana
<400> 68
atggaggagg ctcagtcaga tctcagcact gagctccctc tgagtcaaga gacgttttca 60
tacttgggga aactccttcc tgagaagctg gttctgttcc cctcactgtc cccagcagca 120
gaggcagtag acgatctgct actcccagaa gatgctgcag actggctaga aagccaagct 180
ggggctcaag gaatatcaga agcccctacg ctagccacct cctggacgct gtcatcctct 240
gtcccttctc agaagaccta cccagcacct atcacttctg tctgggcttc ttgcattctg 300
ggacagccaa gtctgtcacc tacacgtact cccctgaact taacgtgctg ttttgccagc 360
tggcaaaggc ctgtccagtg cagctgtggg tcacctcaac acccccgccc agcacctgtg 420
ttcacaccat ggccatctac cagatgtcag catatgatgg aggtcgtgca gcactgtccc 480
caccttgagt gccgctctga ctatagcgat tgcttagacc ctcctcagca ccttatccag 540
tgggaggaaa cctgcatgct gagtatttgg aggacaccat cactctatga catagtgtgg 600
ggtgccctag gagccaccag aggtcggttc tgactaccac catccacttc aacttcatgt 660
gtaacagctc ctgcatgggg ggcaggaacc catcctcacc atcatcacac tggaagactc 720
caatggtaat ccgctgggac acaacagttt cgaggtgcat atttgtactt gtcctgggag 780
acacagatgt acagaggaag acaatttcca taagaagtgg gagccttgcc ctgagccagg 840
ctcggggagg atcactaagg aacactgccc accagcacca gctcctctac caagccaaag 900
aagaagccac tggatgaaaa atacttcact cttcagatcc atggccatga atgcttcaag 960
atgttcctaa agctcaacga ggccttggag ctcaaggatg cccaggctgg gaagcagcca 1020
gaggggaaca gggctcaatc cagccttccc aagtctaaga aaaggcaatc tacctcccgc 1080
cataaaaaac ttatgttcaa gagagagcag cctgactcag actgat 1126
<210> 69
<211> 369
<212> PRT
<213> Loxodonta africana
<400> 69
Met Glu Glu Ala Gln Ser Asp Leu Ser Thr Glu Leu Pro Leu Ser Gln
1 5 10 15
Glu Thr Phe Ser Tyr Leu Gly Lys Leu Leu Pro Glu Lys Leu Val Leu
20 25 30
Phe Pro Ser Leu Ser Pro Ala Ala Glu Ala Val Asp Asp Leu Leu Leu
35 40 45
Pro Glu Asp Ala Ala Asp Trp Leu Glu Ser Gln Ala Gly Ala Gln Gly
50 55 60
Ile Ser Glu Ala Pro Thr Leu Ala Thr Ser Trp Thr Leu Ser Ser Ser
65 70 75 80
Val Pro Ser Gln Lys Thr Tyr Pro Ala Pro Ile Thr Ser Val Trp Ala
85 90 95
Ser Cys Ile Leu Gly Gln Pro Ser Leu Ser Pro Thr Arg Thr Pro Leu
100 105 110
Asn Leu Thr Cys Cys Phe Ala Ser Trp Gln Arg Pro Val Gln Cys Ser
115 120 125
Cys Gly Ser Pro Gln His Pro Arg Pro Ala Pro Val Phe Thr Pro Trp
130 135 140
Pro Ser Thr Arg Cys Gln His Met Met Glu Val Val Gln His Cys Pro
145 150 155 160
His Leu Glu Cys Arg Ser Asp Tyr Ser Asp Cys Leu Asp Pro Pro Gln
165 170 175
His Leu Ile Gln Trp Glu Glu Thr Cys Met Leu Ser Ile Trp Arg Thr
180 185 190
Pro Ser Leu Tyr Asp Ile Val Trp Gly Ala Leu Gly Ala Thr Arg Gly
195 200 205
Arg Phe Leu Pro Pro Ser Thr Ser Thr Ser Cys Val Thr Ala Pro Ala
210 215 220
Trp Gly Ala Gly Thr His Pro His His His His Thr Gly Arg Leu Gln
225 230 235 240
Trp Ser Ala Gly Thr Gln Gln Phe Arg Gly Ala Tyr Leu Tyr Leu Ser
245 250 255
Trp Glu Thr Gln Met Tyr Arg Gly Arg Gln Phe Pro Glu Val Gly Ala
260 265 270
Leu Pro Ala Arg Leu Gly Glu Asp His Gly Thr Leu Pro Thr Ser Thr
275 280 285
Ser Ser Ser Thr Lys Pro Lys Lys Lys Pro Leu Asp Glu Lys Tyr Phe
290 295 300
Thr Leu Gln Ile His Gly His Glu Cys Phe Lys Met Phe Leu Lys Leu
305 310 315 320
Asn Glu Ala Leu Glu Leu Lys Asp Ala Gln Ala Gly Lys Gln Pro Glu
325 330 335
Gly Asn Arg Ala Gln Ser Ser Leu Pro Lys Ser Lys Lys Arg Gln Ser
340 345 350
Thr Ser Arg His Lys Lys Leu Met Phe Lys Arg Glu Gln Pro Asp Ser
355 360 365
Asp
<210> 70
<211> 1154
<212> DNA
<213> Loxodonta africana
<400> 70
aatggaggag ccccagtcag atctcagcac tgagctccct ctgagtcaag agaccttttc 60
atacttgggg aaactccttc ctgagaagct ggttctgtcc ccaccactgt ccccagcagt 120
ggaggtagca gacgatctgc tactcccaga agatgctgca gactggctag aaagccaagc 180
tggggctcaa ggaatatcag tagcccctgc accagcctct cctgagccag ccacctcctg 240
gacactgtca tcctctgtcc cttctcagaa gacctacccc agcatctatg gtttccatct 300
gggcttcttg cattctggga cagccaagtc catcacctac atgtactccc ctgaccttaa 360
caagctgttt tgacagctag caaagacctg tccagtgcag ccgtgggtca cctcaccaac 420
cctgcccagc acctgtgttc acaccatggc catttaccat aagtcagcat atgacggcgg 480
ttgtgcagca ctgcccccac cttgggcgct gctctgacta tagcgatggc ctcgtccctc 540
ctcagcacct catccagcgg ggagaaaacc tgcgtgctga gtatttggag gacactatca 600
ctctttgaca tagtgtgggg tgccctatga gccaccagag gtcggtgccc tatgagccac 660
cagaggtcgg ttctgactac caccatccac ttcatgtgta acagctcctg cagcaaccca 720
tcctcaccat catcacactg gaagactcca atggtaatct gctgggatgc aacaggttcg 780
aggtgcatat ttgtacctgt cctgggagag gcagatgtat agaggaagac aatttccaca 840
tgaagtggga gccttgcccc gagctaccct ctgggaggat cactaagcga gtgctgccca 900
ccagcaccag ctcctctacc aagccaaaga agccgccact ggatgaaaga tatttcaccc 960
ttcagatccg tggacatgaa tgctacaaga tgttctagag ctgaatgcgg ccttggagct 1020
gaaggatgcc gaggctggga agcagccaga ggggagcagg gctcaattca gccttcccaa 1080
gccttagaaa gggcaatcta cctcccacca taaaaaaaca aacattcaag agagaagggc 1140
ctgactcaga ctaa 1154
<210> 71
<211> 371
<212> PRT
<213> Loxodonta africana
<400> 71
Met Glu Glu Pro Gln Ser Asp Leu Ser Thr Glu Leu Pro Leu Ser Gln
1 5 10 15
Glu Thr Phe Ser Tyr Leu Gly Lys Leu Leu Pro Glu Lys Leu Val Leu
20 25 30
Ser Pro Pro Leu Ser Pro Ala Val Glu Val Ala Asp Asp Leu Leu Leu
35 40 45
Pro Glu Asp Ala Ala Asp Trp Leu Glu Ser Gln Ala Gly Ala Gln Gly
50 55 60
Ile Ser Val Ala Pro Ala Pro Ala Ser Pro Glu Pro Ala Thr Ser Trp
65 70 75 80
Thr Leu Ser Ser Ser Val Pro Ser Gln Lys Thr Tyr Pro Ser Ile Tyr
85 90 95
Gly Phe His Leu Gly Phe Leu His Ser Gly Thr Ala Lys Ser Ile Thr
100 105 110
Tyr Met Tyr Ser Pro Asp Leu Asn Lys Leu Phe Gln Leu Ala Lys Thr
115 120 125
Cys Pro Val Gln Pro Trp Val Thr Ser Pro Thr Leu Pro Ser Thr Cys
130 135 140
Val His Thr Met Ala Ile Tyr His Lys Ser Ala Tyr Asp Gly Gly Cys
145 150 155 160
Ala Ala Leu Pro Pro Pro Trp Ala Leu Leu Leu Arg Trp Pro Arg Pro
165 170 175
Ser Ser Ala Pro His Pro Ala Gly Arg Lys Pro Ala Cys Val Phe Gly
180 185 190
Gly His Tyr His Ser Leu Thr Cys Gly Val Pro Tyr Glu Pro Pro Glu
195 200 205
Val Gly Ala Leu Ala Thr Arg Gly Arg Phe Leu Pro Pro Ser Thr Ser
210 215 220
Cys Val Thr Ala Pro Ala Ala Thr His Pro His His His His Thr Gly
225 230 235 240
Arg Leu Gln Trp Ser Ala Gly Met Gln Gln Val Arg Gly Ala Tyr Leu
245 250 255
Tyr Leu Ser Trp Glu Arg Gln Met Tyr Arg Gly Arg Gln Phe Pro His
260 265 270
Glu Val Gly Ala Leu Pro Arg Ala Thr Leu Trp Glu Asp His Ala Ser
275 280 285
Ala Ala His Gln His Gln Leu Leu Tyr Gln Ala Lys Glu Ala Ala Thr
290 295 300
Gly Lys Ile Phe His Pro Ser Asp Pro Trp Thr Met Leu Gln Asp Val
305 310 315 320
Leu Glu Leu Asn Ala Ala Leu Glu Leu Lys Asp Ala Glu Ala Gly Lys
325 330 335
Gln Pro Glu Gly Ser Arg Ala Gln Phe Ser Leu Pro Lys Pro Lys Gly
340 345 350
Gln Ser Thr Ser His His Lys Lys Thr Asn Ile Gln Glu Arg Arg Ala
355 360 365
Leu Arg Leu
370
<210> 72
<211> 1127
<212> DNA
<213> Loxodonta africana
<400> 72
agtggaggag cctcagtcag atctgagcat tgagctccct ctgagtcaag agacattttc 60
atacttgggg aaactccttt ctgagaagct ggttctatcc ccctcactgt ccccagcagc 120
ggaggcagta gtcaatctgc tactcccaga agatgctgca gactggctag aaagccaagg 180
tggggctcaa ggaatatcag aagcacctac actagccacc tcctggacgc tgtcatcctc 240
tgttccttct cagaagacct acccagcacc tatcatttct gtctgggctt cttgcattct 300
gggacagcca agtccgtcac ctacacgtac tcccctgaac ttaacatgct gttttgccag 360
ctggcaaagg cctgtccagt gcagccgtgg gtcacctcaa cacccccgcc cagcacctgt 420
gttcacacca tggccatcta ccagacgtca gcatatgatg gaggtcgtga agcactgccc 480
ccaccttgag tgccgctctg actatagcga ttgcttggac cctcctcagc acctcatgca 540
gtgggaggaa acctgcatgc tgagtatttg gaggacacca tcactctatg acatagtgtg 600
gggtgcccta ggagccacca gaggtcggtt ctgactacca ccatccactt caacttcatg 660
tgtaacagct cctgcatggg gcgcatgaac ccattctcac cattatgaca atggaagact 720
ccaatggtaa tccgctggga cacaacagtt tcgaggtgca tatttgtacc tgtcctggga 780
gacacagatg tacagaggaa gacaatttcc acaacaagtg ggagccttgc cctgagccac 840
cctctgggag gatcactacg caaacactgc ccaccagcac cagctcctct acgaagccaa 900
agaagaagcc actggatgaa aaatacttca cccttcagat ccatgggcat gaatgcttca 960
agatgttcct aaagctcaac gaggccttgg agctgaagga tgcccaggct gggaagcagc 1020
cagaggggaa cagggctcaa tccagccttc ccaagtctaa gaaaaggcaa tctacctccc 1080
accataaaaa actaacgttc aagagagagc agcctgactc agactga 1127
<210> 73
<211> 366
<212> PRT
<213> Loxodonta africana
<400> 73
Val Glu Glu Pro Gln Ser Asp Leu Ser Ile Glu Leu Pro Leu Ser Gln
1 5 10 15
Glu Thr Phe Ser Tyr Leu Gly Lys Leu Leu Ser Glu Lys Leu Val Leu
20 25 30
Ser Pro Ser Leu Ser Pro Ala Ala Glu Ala Val Val Asn Leu Leu Leu
35 40 45
Pro Glu Asp Ala Ala Asp Trp Leu Glu Ser Gln Gly Gly Ala Gln Gly
50 55 60
Ile Ser Glu Ala Pro Thr Leu Ala Thr Ser Trp Thr Leu Ser Ser Ser
65 70 75 80
Val Pro Ser Gln Lys Thr Tyr Pro Ala Pro Ile Ile Ser Val Trp Ala
85 90 95
Ser Cys Ile Leu Gly Gln Pro Ser Pro Ser Pro Thr Arg Thr Pro Leu
100 105 110
Asn Leu Thr Cys Cys Phe Ala Ser Trp Gln Arg Pro Val Gln Cys Ser
115 120 125
Arg Gly Ser Pro Gln His Pro Arg Pro Ala Pro Val Phe Thr Pro Trp
130 135 140
Pro Ser Thr Arg Arg Gln His Met Met Glu Val Val Lys His Cys Pro
145 150 155 160
His Leu Glu Cys Arg Ser Asp Tyr Ser Asp Cys Leu Asp Pro Pro Gln
165 170 175
His Leu Met Gln Trp Glu Glu Thr Cys Met Leu Ser Ile Trp Arg Thr
180 185 190
Pro Ser Leu Tyr Asp Ile Val Trp Gly Ala Leu Gly Ala Thr Arg Gly
195 200 205
Arg Phe Leu Pro Pro Ser Thr Ser Thr Ser Cys Val Thr Ala Pro Ala
210 215 220
Trp Gly Ala Thr His Ser His His Tyr Asp Asn Gly Arg Leu Gln Trp
225 230 235 240
Ser Ala Gly Thr Gln Gln Phe Arg Gly Ala Tyr Leu Tyr Leu Ser Trp
245 250 255
Glu Thr Gln Met Tyr Arg Gly Arg Gln Phe Pro Gln Gln Val Gly Ala
260 265 270
Leu Pro Ala Thr Leu Trp Glu Asp His Tyr Ala Asn Thr Ala His Gln
275 280 285
His Gln Leu Leu Tyr Glu Ala Lys Glu Glu Ala Thr Gly Lys Ile Leu
290 295 300
His Pro Ser Asp Pro Trp Ala Met Leu Gln Asp Val Pro Lys Ala Gln
305 310 315 320
Arg Gly Leu Gly Ala Glu Gly Cys Pro Gly Trp Glu Ala Ala Arg Gly
325 330 335
Glu Gln Gly Ser Ile Gln Pro Ser Gln Val Glu Lys Ala Ile Tyr Leu
340 345 350
Pro Pro Lys Thr Asn Val Gln Glu Arg Ala Ala Leu Arg Leu
355 360 365
<210> 74
<211> 1127
<212> DNA
<213> Loxodonta africana
<400> 74
aatggaggag cctcagtcag atctcagcac tgagctccct ctgagtcaag agacattttc 60
atacttgggg aaactccttc ctgagaagct ggttctgtcc ccctcactgt ccccagcagc 120
ggaggcagta gatgatctgc tactcccaga agatgctgca gactggctag aaagccaagc 180
tggggctcaa ggaatatcag aagcccctac actagccacc tcctggacgc tgtcatcctc 240
tgtcccttct cagaagacct acccagcacc tatcgtttct gtctgggctt cttgcattct 300
gggacagcca agtctgtcac ctacacgtac tcccctgaac ttaacatgct gttttgccgg 360
ctggcaaagg cctgtccagt gcagctgtgg gtcacctcaa caaccccgcc cagcacctgt 420
gttcacacca tggccatcta ccagacgtca gcatatgatg gaggtcgtga agcactgccc 480
ccaccttgag tgccgctgtg actatagcga ttgcttggac cctcctcagc acctcatcca 540
gtaggaggaa acctgcatgc tgagtatttg gaggacacca tcactctatg acatagtgtg 600
gggtgcccta ggagccacca gaggtcggtt ctgactacca ccatccactt caacttcatg 660
tgtaacagct cctgcatggg gggcatgaac ccatcctcac catcatcact ctggaatact 720
ccaatggtaa tccgctggga cacaacagtt tcgaggtgca tatttgtacc tgtcctggga 780
gacacagatg tacagaggaa gacaatttcc agaagaagtg ggagccttgc cctgagccac 840
cctctgggag gatcactaag caaacactgc ccaccagcac cagctcctct atcaagccaa 900
agaagaagcc actggatgaa aaatacttca cccttcagat ccatggccat gaatgtttca 960
agatgttcct aaagctcaac gaggccttgg agctgaagga tgcccaggct gggaagcaac 1020
caggggggag cagggctcaa tccagccttc ccaagtctaa gaaaaggcaa tctatctccc 1080
accataaaaa actaatgttc aagaaagagc agcctgactc agactga 1127
<210> 75
<211> 364
<212> PRT
<213> Loxodonta africana
<400> 75
Met Glu Glu Pro Gln Ser Asp Leu Ser Thr Glu Leu Pro Leu Ser Gln
1 5 10 15
Glu Thr Phe Ser Tyr Leu Gly Lys Leu Leu Pro Glu Lys Leu Val Leu
20 25 30
Ser Pro Ser Leu Ser Pro Ala Ala Glu Ala Val Asp Asp Leu Leu Leu
35 40 45
Pro Glu Asp Ala Ala Asp Trp Leu Glu Ser Gln Ala Gly Ala Gln Gly
50 55 60
Ile Ser Glu Ala Pro Thr Leu Ala Thr Ser Trp Thr Leu Ser Ser Ser
65 70 75 80
Val Pro Ser Gln Lys Thr Tyr Pro Ala Pro Ile Val Ser Val Trp Ala
85 90 95
Ser Cys Ile Leu Gly Gln Pro Ser Leu Ser Pro Thr Arg Thr Pro Leu
100 105 110
Asn Leu Thr Cys Cys Phe Ala Gly Trp Gln Arg Pro Val Gln Cys Ser
115 120 125
Cys Gly Ser Pro Gln Gln Pro Arg Pro Ala Pro Val Phe Thr Pro Trp
130 135 140
Pro Ser Thr Arg Arg Gln His Met Met Glu Val Val Lys His Cys Pro
145 150 155 160
His Leu Glu Cys Arg Cys Asp Tyr Ser Asp Cys Leu Asp Pro Pro Gln
165 170 175
His Leu Ile Gln Glu Glu Thr Cys Met Leu Ser Ile Trp Arg Thr Pro
180 185 190
Ser Leu Tyr Asp Ile Val Trp Gly Ala Leu Gly Ala Thr Arg Gly Arg
195 200 205
Phe Leu Pro Pro Ser Thr Ser Thr Ser Cys Val Thr Ala Pro Ala Trp
210 215 220
Gly Ala Thr His Pro His His His His Ser Gly Ile Leu Gln Trp Ser
225 230 235 240
Ala Gly Thr Gln Gln Phe Arg Gly Ala Tyr Leu Tyr Leu Ser Trp Glu
245 250 255
Thr Gln Met Tyr Arg Gly Arg Gln Phe Pro Glu Glu Val Gly Ala Leu
260 265 270
Pro Ala Thr Leu Trp Glu Asp His Ala Asn Thr Ala His Gln His Gln
275 280 285
Leu Leu Tyr Gln Ala Lys Glu Glu Ala Thr Gly Lys Ile Leu His Pro
290 295 300
Ser Asp Pro Trp Pro Met Phe Gln Asp Val Pro Lys Ala Gln Arg Gly
305 310 315 320
Leu Gly Ala Glu Gly Cys Pro Gly Trp Glu Ala Thr Arg Gly Glu Gln
325 330 335
Gly Ser Ile Gln Pro Ser Gln Val Glu Lys Ala Ile Tyr Leu Pro Pro
340 345 350
Lys Thr Asn Val Gln Glu Arg Ala Ala Leu Arg Leu
355 360
<210> 76
<211> 1127
<212> DNA
<213> Loxodonta africana
<400> 76
aatggaggag cctcagtcag atctcagcac tgagctccct ctgagtcaag ggacgttttc 60
atacttgggg aaactccttc ctgagaagct ggttctgttc ccctcactgt ccccagcagc 120
agaggcaata gacgatctgc tactcccaga agatgctgca gactggctag aaagccaagc 180
tggggctcaa ggactatcag aagcctctac actagccacc tcctggacgc tgtcatcctc 240
tgtcccttct cagaagacct acccagcacc tatcgtttct gtctgggctt cttgcattct 300
gggacagcca agttcgtcac ctacacgtac tcccctgaac ttaacatgct gttttgccag 360
ctggcaaagg cctgtccagt gcagctgtgg gtcacctcaa cacccctgcc cagcacctgt 420
gttcacacca tggccatcta ccagacgtca gcatatgatg gaggtcgtga agcactgccc 480
ccaccttgag tgccgctctg actatagcga ttgcttggac cctcctcagc acctcatcca 540
gtgggaggaa acctgcatgc tgagtatttg gaggacacca tcactctatg acatagtgtg 600
gggtgcccta ggagccacca gaggtcggtt ctgactacca ccatccactt caacttcatg 660
tgtaacagct cctgcatggg gggcaggaag ccatcctcac catcatcaca ctggaaaact 720
ccaatggtaa tccgctgaga cacaacagtt tcgaggtgca tatttgtact tgtcctggga 780
gacacagata tacagaggaa gacaatttcc ataagaagtg ggagccttgc cctgagccag 840
gctcggggag gatcactaag cgaacactgc ccaccagcac cagctcctct accaagccaa 900
agaagaagcc actggatgaa aaatacttca ctcttcagat ccatggccat gaatgcttca 960
agatgttcct aaagctcaac gaggccttgg agctcaagga tgcccagact gggaagcagc 1020
cagaggggaa cagggctcaa tccagccttc ccaagtctaa gaaaaggcaa tctacctccc 1080
gccataaaaa acttatgttc aagagagagc agcctgactc agactga 1127
<210> 77
<211> 365
<212> PRT
<213> Loxodonta africana
<400> 77
Met Glu Glu Pro Gln Ser Asp Leu Ser Thr Glu Leu Pro Leu Ser Gln
1 5 10 15
Gly Thr Phe Ser Tyr Leu Gly Lys Leu Leu Pro Glu Lys Leu Val Leu
20 25 30
Phe Pro Ser Leu Ser Pro Ala Ala Glu Ala Ile Asp Asp Leu Leu Leu
35 40 45
Pro Glu Asp Ala Ala Asp Trp Leu Glu Ser Gln Ala Gly Ala Gln Gly
50 55 60
Leu Ser Glu Ala Ser Thr Leu Ala Thr Ser Trp Thr Leu Ser Ser Ser
65 70 75 80
Val Pro Ser Gln Lys Thr Tyr Pro Ala Pro Ile Val Ser Val Trp Ala
85 90 95
Ser Cys Ile Leu Gly Gln Pro Ser Ser Ser Pro Thr Arg Thr Pro Leu
100 105 110
Asn Leu Thr Cys Cys Phe Ala Ser Trp Gln Arg Pro Val Gln Cys Ser
115 120 125
Cys Gly Ser Pro Gln His Pro Cys Pro Ala Pro Val Phe Thr Pro Trp
130 135 140
Pro Ser Thr Arg Arg Gln His Met Met Glu Val Val Lys His Cys Pro
145 150 155 160
His Leu Glu Cys Arg Ser Asp Tyr Ser Asp Cys Leu Asp Pro Pro Gln
165 170 175
His Leu Ile Gln Trp Glu Glu Thr Cys Met Leu Ser Ile Trp Arg Thr
180 185 190
Pro Ser Leu Tyr Asp Ile Val Trp Gly Ala Leu Gly Ala Thr Arg Gly
195 200 205
Arg Phe Leu Pro Pro Ser Thr Ser Thr Ser Cys Val Thr Ala Pro Ala
210 215 220
Trp Gly Ala Gly Ser His Pro His His His His Thr Gly Lys Leu Gln
225 230 235 240
Trp Ser Ala Glu Thr Gln Gln Phe Arg Gly Ala Tyr Leu Tyr Leu Ser
245 250 255
Trp Glu Thr Gln Ile Tyr Arg Gly Arg Gln Phe Pro Glu Val Gly Ala
260 265 270
Leu Pro Ala Arg Leu Gly Glu Asp His Ala Asn Thr Ala His Gln His
275 280 285
Gln Leu Leu Tyr Gln Ala Lys Glu Glu Ala Thr Gly Lys Ile Leu His
290 295 300
Ser Ser Asp Pro Trp Pro Met Leu Gln Asp Val Pro Lys Ala Gln Arg
305 310 315 320
Gly Leu Gly Ala Gln Gly Cys Pro Asp Trp Glu Ala Ala Arg Gly Glu
325 330 335
Gln Gly Ser Ile Gln Pro Ser Gln Val Glu Lys Ala Ile Tyr Leu Pro
340 345 350
Pro Lys Thr Tyr Val Gln Glu Arg Ala Ala Leu Arg Leu
355 360 365
Claims (49)
- 암 세포를 (a) 코끼리 p53 단백질을 각각 암호화하는 하나 이상의 핵산 서열, 또는 (b) 하나 이상의 코끼리 p53 단백질과 접촉시킴을 포함하고, 이에 의해 암을 저해하는, 암의 저해 방법.
- 제1항에 있어서, 상기 암 세포를, 코끼리 p53 단백질을 각각 암호화하는 하나 이상의 핵산 서열과 접촉시킴을 포함하는, 방법.
- 제2항에 있어서, 코끼리 p53 단백질을 암호화하는 핵산 서열이 레트로유전자인, 방법.
- 제2항에 있어서, 코끼리 p53 단백질을 암호화하는 핵산 서열이 선조(ancestral) 유전자인, 방법.
- 제2항에 있어서, 상기 암 세포를, 코끼리 p53 단백질을 각각 암호화하는 다수의 핵산 서열과 접촉시킴을 포함하는, 방법.
- 제5항에 있어서, 상기 다수의 핵산 서열이 다수의 상이한 레트로유전자를 포함하는, 방법.
- 제6항에 있어서, 상기 다수의 핵산 서열 중 적어도 하나가 선조 유전자를 포함하는, 방법.
- 제1항 내지 제7항 중 어느 한 항에 있어서, 상기 하나 이상의 핵산 서열이 RNA 또는 DNA를 포함하는, 방법.
- 제3항 또는 제6항에 있어서, 상기 레트로유전자가 서열 번호 4, 서열 번호 6, 서열 번호 8, 서열 번호 10, 서열 번호 12, 서열 번호 14, 서열 번호 16, 서열 번호 18, 서열 번호 20, 서열 번호 22, 서열 번호 24, 서열 번호 26, 서열 번호 28, 서열 번호 30, 서열 번호 32, 서열 번호 34, 서열 번호 36, 서열 번호 38, 서열 번호 40, 서열 번호 42, 서열 번호 44, 서열 번호 46, 서열 번호 48, 서열 번호 50, 서열 번호 52, 서열 번호 54, 서열 번호 56, 서열 번호 58, 서열 번호 60, 서열 번호 62, 서열 번호 64, 서열 번호 66, 서열 번호 68, 서열 번호 70, 서열 번호 72, 서열 번호 74, 또는 서열 번호 76의 핵산 서열을 포함하는, 방법.
- 제4항 또는 제7항에 있어서, 상기 선조 유전자가 서열 번호 2의 핵산 서열을 포함하는, 방법.
- 제1항에 있어서, 상기 암 세포를 하나 이상의 코끼리 p53 단백질과 접촉시킴을 포함하는, 방법.
- 제11항에 있어서, 상기 암 세포를 하나의 코끼리 p53 단백질과 접촉시킴을 포함하는, 방법.
- 제12항에 있어서, 상기 코끼리 p53 단백질이 레트로유전자로 암호화되는, 방법.
- 제13항에 있어서, 상기 코끼리 p53 단백질이 선조 유전자로 암호화되는, 방법.
- 제11항에 있어서, 상기 암 세포를 다수의 상이한 코끼리 p53 단백질과 접촉시킴을 포함하는, 방법.
- 제15항에 있어서, 상기 다수의 상이한 코끼리 p53 단백질이 다수의 상이한 레트로유전자로 암호화되는, 방법.
- 제16항에 있어서, 상기 다수의 상이한 코끼리 p53 단백질 중 적어도 하나가 선조 p53 단백질인, 방법.
- 제13항 또는 제16항에 있어서, 상기 P53 단백질이 서열 번호 5, 서열 번호 7, 서열 번호 9, 서열 번호 11, 서열 번호 13, 서열 번호 15, 서열 번호 17, 서열 번호 19, 서열 번호 21, 서열 번호 23, 서열 번호 25, 서열 번호 27, 서열 번호 29, 서열 번호 31, 서열 번호 33, 서열 번호 35, 서열 번호 37, 서열 번호 39, 서열 번호 41, 서열 번호 43, 서열 번호 45, 서열 번호 47, 서열 번호 49, 서열 번호 51, 서열 번호 53, 서열 번호 55, 서열 번호 57, 서열 번호 59, 서열 번호 61, 서열 번호 63, 서열 번호 65, 서열 번호 67, 서열 번호 69, 서열 번호 71, 서열 번호 73, 서열 번호 75, 및 서열 번호 77의 아미노산 서열을 포함하는, 방법.
- 제14항 또는 제17항에 있어서, 상기 p53 단백질이 서열 번호 3의 아미노산 서열을 포함하는, 방법.
- 제1항 내지 제19항 중 어느 한 항에 있어서, 상기 하나 이상의 핵산 서열 또는 상기 하나 이상의 코끼리 p53 단백질이 조성물의 형태이고, 이러한 조성물이 약제학적으로 허용되는 담체를 포함하는, 방법.
- 제20항에 있어서, 상기 조성물이 리포솜을 포함하는, 방법.
- 제21항에 있어서, 상기 하나 이상의 핵산 서열 또는 하나 이상의 p53 단백질이 상기 리포솜 내로 캡슐화되는, 방법.
- 제20항에 있어서, 상기 조성물이 나노입자를 포함하는, 방법.
- 제23항에 있어서, 상기 나노입자가 유기 물질, 무기 물질, 지질, 중합체, 금속, 및 탄소 나노구조로 이루어진 그룹으로부터 선택된 하나 이상의 필러를 포함하는, 방법.
- 제23항 또는 제24항에 있어서, 상기 나노입자가 리포솜 내로 캡슐화된 코끼리 p53 단백질 또는 코끼리 TP53 핵산을 포함하는, 방법.
- 제23항 내지 제25항 중 어느 한 항에 있어서, 상기 나노입자가 망상내피계와의 상호작용을 감소시키기 위해 모이어티로 데코레이팅된(decorated) 외부 표면을 포함하는, 방법.
- 제26항에 있어서, 상기 모이어티가 폴리에틸렌 글리콜을 포함하는, 방법.
- 제26항에 있어서, 상기 모이어티가 표적화 모이어티를 포함하는, 방법.
- 제28항에 있어서, 상기 표적화 모이어티가 상기 암 세포에 대한 상기 나노입자의 친화도를 증가시키는, 방법.
- 제20항 내지 제29항 중 어느 한 항에 있어서, 상기 조성물이 소분자 화학요법제, 단클론성 항체, 및 영상화제(imaging agent)로 이루어진 그룹으로부터 선택된 하나 이상의 첨가제를 추가로 포함하는, 방법.
- 제30항에 있어서, 상기 영상화제가 조영제(contrast agent), 당, 철 착물, 또는 가돌리늄(Gd)을 포함하는, 방법.
- 제1항 내지 제31항 중 어느 한 항에 있어서, 상기 암 세포가 시험관내 또는 생체내에 존재하는, 방법.
- 제1항 내지 제32항 중 어느 한 항에 있어서, 상기 암 세포가 포유동물로부터 유래되는, 방법.
- 제33항에 있어서, 상기 포유동물이 사람인, 방법.
- 약제학적으로 허용되는 담체 및 (a) 코끼리 p53 단백질을 각각 암호화하는 하나 이상의 핵산 서열 또는 (b) 하나 이상의 코끼리 p53 단백질을 포함하는 조성물.
- 제34항에 있어서, 코끼리 p53 단백질을 각각 암호화하는 하나 이상의 핵산 서열을 포함하는, 조성물.
- 제34항 또는 제35항에 있어서, 상기 상기 하나 이상의 핵산 서열이 RNA 또는 DNA를 포함하는, 조성물.
- 제34항에 있어서, 하나 이상의 코끼리 p53 단백질을 포함하는, 조성물.
- 제34항에 있어서, 리포솜을 포함하는, 조성물.
- 제38항에 있어서, 상기 하나 이상의 핵산 서열 또는 하나 이상의 P53 단백질이 상기 리포솜 내로 캡슐화되는, 조성물.
- 제34항에 있어서, 나노입자를 포함하는, 조성물.
- 제40항에 있어서, 상기 나노입자가 유기 물질, 무기 물질, 지질, 중합체, 금속, 및 탄소 나노구조로 이루어진 그룹으로부터 선택된 하나 이상의 필러를 포함하는, 조성물.
- 제40항 또는 제41항에 있어서, 상기 하나 이상의 핵산 서열 또는 하나 이상의 p53 단백질이 리포솜 내에 캡슐화되는, 조성물.
- 제40항 내지 제42항 중 어느 한 항에 있어서, 상기 나노입자가 망상내피계와의 상호작용을 감소시키기 위해 모이어티로 데코레이팅된 외부 표면을 포함하는, 조성물.
- 제43항에 있어서, 상기 모이어티가 폴리에틸렌 글리콜을 포함하는, 조성물.
- 제43항에 있어서, 상기 모이어티가 표적화 모이어티를 포함하는, 조성물.
- 제45항에 있어서, 상기 표적화 모이어티가 상기 암 세포에 대한 상기 나노입자의 친화도를 증가시키는, 조성물.
- 제34항 내지 제46항 중 어느 한 항에 있어서, 소분자 화학요법제, 단클론성 항체, 및 영상화제로 이루어진 그룹으로부터 선택된 하나 이상의 첨가제를 추가로 포함하는, 조성물.
- 제47항에 있어서, 상기 영상화제가 조영제, 당, 철 착물, 또는 가돌리늄(Gd)를 포함하는, 조성물.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201562239103P | 2015-10-08 | 2015-10-08 | |
| US62/239,103 | 2015-10-08 | ||
| US201662379179P | 2016-08-24 | 2016-08-24 | |
| US62/379,179 | 2016-08-24 | ||
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| CN104208066B (zh) * | 2013-06-03 | 2016-06-15 | 中国科学院遗传与发育生物学研究所 | 哌嗪衍生物作为p53分子调节剂的用途 |
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| Title |
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| "TP53 Copy Number Expansion Correlates with the Evolution of Increased Body Size and an Enhanced DNA Damage Response in Elephants." BioRxiv. (06. Oct. 2015).* * |
| Aleah F. Caulin. Peto's Paradox and the Evolution of Cancer Suppression. University of Pennsylvania. Ph.D. Thesis.(2014.01.)* * |
| NCBI.GenBank: KF715863.1 (Loxodonta africana TP53 retrogene 9 genomic sequence) * |
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