JP4416650B2 - 新規なポリヌクレオチドおよびポリペプチド配列ならびにその使用 - Google Patents
新規なポリヌクレオチドおよびポリペプチド配列ならびにその使用 Download PDFInfo
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Description
Kunkelら、(1987) Meth. Enzymol.、154:367〜382頁 Shimaokaら、(2002) Annu. Rev. Biophys. Biomol. Struc.、31:485〜516頁 WangおよびSpringer、(1998) Immunol. Rev.、163:197〜215頁 Cassanovaら、(1998) J. Virol.、72:6244〜6246頁 AmzelおよびPoljak、(1979) Annu. Rev. Biochem.、48:961〜997頁 Garcia、(1999) Annu. Rev. Immunol.、17:369〜397頁 HenneckeおよびWiley、(2001) Cell、104:1〜4頁 de Vosら、(1992) Science、255:306〜312頁 DellerおよびJones、(2000) Curr. Opin. Struc. Biol.、10:213〜219頁 ChothiaおよびJones、(1997) Annu. Rev. Biochem.、66:823〜862頁
使用した細胞系は、American Type Culture Collection(ATCC、米国バージニア州Manassas)から入手し、その増殖に使用した培地は、ギブコ社、米国ニューヨーク州Grand Island、から購入した。細胞系およびそのそれぞれの増殖培地(括弧に示す)は以下の通りであった:AGS、ヒト胃腺癌細胞系、(F-12);293、アデノウイルス5 DNAで形質転換したヒト腎臓上皮細胞系(ダルベッコ改変イーグル培地(DMEM));KKVR(イスコフのDMEM);RF-1、ヒト胃腺癌細胞系(LeibovitzのL-15);NCI-SNU-1、NCI-SNU-16、NCI-N87、ヒト肝臓胃悪性腫瘍細胞系およびKatoIII、ヒト胃悪性腫瘍(RPMI)。培地は全て、2mMのL-グルタミン(ギブコ、米国ニューヨーク州Grand Island)および10%ウシ胎仔血清(FBS、Hyclone、米国ユタ州Logan)を補充した。しかし、KatoIIIおよびKKVRは、20%FBSおよびNCI-N87中で増殖させ、KKVR増殖培地にはさらに1.5g/Lの炭酸水素ナトリウムを補充した。
本実施例は、差次的に発現した新規な癌遺伝子の同定を示す。手短に言えば、マウス造血幹細胞サブトラクティブcDNAライブラリーを使用した。Phillipsら、(2000) Science、288:1635〜1640頁。このライブラリーから約7,500個のESTをDNAマイクロアレイ上に置き、様々なマウス癌細胞系および対応する正常組織から調製したcDNAとハイブリダイズさせた。
本実施例は、正常組織および癌組織でのhS30-21616/DEGAの発現を示す。手短に言えば、multiple tissue Northern(BD Biosciences/Clonetech、米国カリフォルニア州Palo Alto)を使用するノーザンブロット分析を実施して正常組織および癌組織でのhS30-21616/DEGAの発現を評価した。スクリーニングした正常組織には、脳、心臓、骨格筋、大腸、胸腺、脾臓、腎臓、肝臓、小腸、胎盤、肺、末梢血白血球、副腎、膀胱、骨髄、リンパ節、前立腺、脊髄、胃、甲状腺、気管、子宮、および舌が含まれる。これらの組織の大部分で、hS30-21616/DEGAの発現は非常に低かった。
本実施例は、cDNAドットブロットを使用し患者試料におけるS30-21616/DEGAの発現の癌プロファイリングアレイ(CPA)分析を示す。手短に言えば、メーカー指示書に従って、様々な腫瘍および正常組織において、(CPA)IおよびII(BD Biosciences Clontech、米国カリフォルニア州Palo Alto)を、ORFヌクレオチド1540〜2045(図1に基づいて番号付け)を包含するcDNA断片によってプローブした。プローブは、[α-32P]-dCTP(PerkinElmer Life Sciences、Inc.、米国マサチューセッツ州ボストン)を使用して標識し、Prime-It(登録商標)IIキット(Stratagene Cloning Systems、米国カリフォルニア州La Jolla)を使用して単離した。CPA IおよびIIは、それぞれ個々の癌患者から得た241個および160個の腫瘍組織および対応する正常組織から得た規準化cDNAを含むナイロンアレイである。CPA Iによって表される組織は以下を含む:乳房、子宮、大腸、胃、卵巣、肺、腎臓、直腸、甲状腺、子宮頚部、小腸、膵臓、および前立腺。これらの組織の他に、CPA IIは、膀胱、精巣、および皮膚組織を含む。これらのアレイは、正負の対照および9種の癌細胞系:HeLa、Daudi、K-562、HL-60、G-361、A549、Molt-4、SW480、およびRajiから単離したcDNAも含む。
本実施例は、胃腺癌細胞でのDEGAの発現のノーザンブロット分析を示す。胃癌患者試料の45%がその腫瘍中でDEGAの差次的発現を示したが、隣接する正常な胃組織でわずかな発現が示された観察から、DEGAは胃腺癌の少なくとも下位画分の発生または進行で中心的役割を果たし得ることがが示唆される。DEGAが腺癌細胞系、AGS、NCI-SNU-1、NCI-SNU-16、NCI-N87、KATOIII、KKVR、およびRF-1で発現したかどうか判定するためにノーザンブロット分析を実施した。
本実施例は、他の非胃腺癌癌細胞系でのS30-21616/DEGAの発現の癌プロファイリングアレイ(CPA)分析を示す。cDNAドットブロットを使用し、CPA IおよびIIに使用したS30-21616/DEGAプローブおよび条件もまた使用してBD Bioscience社の癌細胞系プロファイリングアレイとハイブリダイズさせた。このアレイは、以下の癌を表す細胞系から得たcDNAを含む:肺(A549、NCI-H-460、NCI-H1299)、大腸(HCT-116、HCT-15、HT-29)、乳(MDA-MB4355、MDA-MB231、MCF7)、卵巣(SK-OV-3)、子宮頚部(HeLa)、前立腺(DU-145、PC-3)、皮膚(SK-MEL-28、SK-MEL-5、SK-NSH、IMR-32、U-87MG)、脳(IMR-32、U-87MG)、腎臓(786-O、ACHN)、肝臓(Hep-G2)、大腸(Colo589)、骨肉腫(U2-OS)、および表皮(A-431)。
本実施例は、S30-21616/DEGAのcDNAクローニングを示す。手短に言えば、ヒトS30-21616/DEGA cDNAをMarathon-Ready(商標)A549、ヒト肺細胞悪性腫瘍系および脾臓のcDNA調製物(BD Biosciences/Clonetech、米国カリフォルニア州Palo Alto)に由来するRT-PCR産生物として増幅した。当該ポリヌクレオチドを増幅するために使用したPCRプライマーは、配列5'ATG TCG TTA CGT GTA CAC ACT CTG3'(配列番号14)のフォワードPCRプライマー1号、および5'TTA AGT GGA CGC CAC AAA AGG TGT G3'(配列番号15)のレバースPCRプライマー2号(Bio-Synthesis Incorporated、米国テキサス州Lewisville、開始コドンおよび終止コドンに下線を引く)である。PCR反応は、使用したポリメラーゼがチタンTaqポリメラーゼ(BD Biosciences/Clonetech、米国カリフォルニア州Palo Alto)であることを除き、当技術分野で周知の標準的RT-PCRプロトコルを使用し実施し、具体的にはMarathon-Ready(商標)のcDNAマニュアルに記載されたRT-PCR条件:94℃で30秒、68℃で2分間を使用した。
本実施例は、293細胞中でのS30-21616/DEGA-EGFP融合構築体の安定した発現、および蛋白質の細胞内局在化を示す。手短に言えば、融合蛋白質を設計し、それによって増幅緑色蛍光蛋白質(enhanced green fluorescent protein, EGFP)をそのC末端に融合した。S30-21616/DEGA ORFをPCR増幅し、pEGFP-N1(BD Biosciences Clontech、米国カリフォルニア州Palo Alto)のXhoI/AgeI部位中にクローン化した。PCR反応は、フォワードプライマー(5'ATC CTC GAG GCG ACC ATA ATG TCG TTA CGT GTA CAC ACT3'、配列番号19) (天然Kozak配列およびXhoI部位(下線)を含み、5'から開始コドンを太字で示した)を使用したことを除いて、S30-21616/DEGAのcDNAクローニングの節に記載されている通りに実施した。使用したリバースプライマー(5'GAT CAC CGG TGC AGT GGA CGC CAC AAA AGG TGT GTC3'、配列番号20)は太字で示した終止コドンのAge I部位(下線)3'を含む。
本実施例は、AGS細胞中でS30-21616/DEGAアンチセンス構築体安定して発現することを示す。S30-21616/DEGAの発現プロフィールは、これが発生またはヒト胃腺癌のサブセットの進行において機能的役割を果たし得ることを示唆する。S30-21616/DEGAの機能的役割に取り組むために、著しいレベルのS30-21616/DEGAのmRNAを発現することが示されているヒトAGS細胞系にトランスフェクトしてアンチセンスS30-21616/DEGA構築体または空ベクターを安定的に発現させた。確立された細胞系を細胞周期、増殖、および腫瘍形成能アッセイでのクローン比較研究に使用した。
本実施例は、ノーザンブロット分析によってAGS/DEGAアンチセンスクローンおよび空ベクタークローンの比較発現を示す。胃腺癌細胞系でのS30-21616/DEGAの発現の効果を判定するために、AGSをアンチセンスS30-21616/DEGAおよび空ベクターによって安定的にトランスフェクトし、標準ノーザンブロッティング手順を実施した。全RNAをMicro-to-Midi Total RNAシステム(InVitrogen Corporation、米国カリフォルニア州Carlsbad)を使用してメーカーによって推奨された通り厳密に単離し、5μgを1.2%の変性ホルムアルデヒドゲル上に溶解し、Nytran(登録商標)SuPerChargeメンブレン(SchleicherおよびSchuell、Inc.、Keene、NH)に移し取った。CPA IおよびII cDNAブロットをプローブするために使用した32Pランダム標識S30-21616/DEGA C末端プローブとブロットをハイブリダイズした。ハイブリダイズは、ExpressHyb(商標)溶液(BD Biosciences Clontech、米国カリフォルニア州Palo Alto)を使用し68℃で1時間実施した。10分ずつ3回の室温洗浄(2×SSC、0.05%SDS)および20分ずつ2回の50℃での洗浄(0.1×SSC、0.1%SDS)を行った。メンブレンを2×SSCで洗い、-70℃で終夜Kodak BioMax MRフィルムに曝露した(Eastman Kodak Company、米国ニューヨーク州ロチェスター)。
本実施例は、AGS/DEGAアンチセンスクローンおよび空ベクタークローンのDNA含有量/細胞周期プロフィールをフローサイトメトリ分析によってを示す。DNA含有量、したがって細胞周期プロフィールを測定するためにフローサイトメトリを使用した。AGS空ベクターおよびS30-21616/DEGAアンチセンスクローンを同時に起こらないように血清含有増殖培地で増殖し、トリプシン処理し、PBSで1回洗浄し、DNA QC Particlesキット(カタログ番号349523、Becton Dickinson)に含まれていたヨウ化プロピジウム溶液によって室温暗所で10分間染色した。続いて、Becton Dickinson FACSVantage(商標)フローサイトメータによりDNA QC particlesキットに記載されたパラメータを使用し細胞を分析した。細胞サイズを光学顕微鏡によって評価した。
本実施例は、DEGA発現細胞のin-vivo腫瘍形成能研究を示す。AGS/空ベクターとAGS/DEGAアンチセンスクローンとの間に観察された細胞周期プロフィールの差より、in vivoでの細胞増殖の差も推定される。AGS細胞は、ヌードマウスで腫瘍性であるので、S30-21616/DEGAの発現を抑制するS30-21616/DEGAアンチセンスの効果、したがってAGS細胞の腫瘍化の可能性への負の影響を以下に実施した。AGSクローンを増殖培地に懸濁させ、氷冷し、MATRIGEL(商標)(Collaborative Research Biochemicals、米国マサチューセッツ州Bedford)と1:1(v/v)の割合で完全に混合した。MATRIGEL(商標)は、Engelbroth-Holm-Swarmマウス肉腫に由来し、この肉腫は、ECM蛋白質:ラミニン、コラーゲンIV、ナイドジェン/エナクチン、およびプロテオグリカンの豊かな供給源であることが判明している(12)。細胞系と混合すると、MATRIGEL(商標)は腫瘍形成(27)を強化する。各胸腺欠損(nu/nu)マウス(Charles River Laboratories、米国マサチューセッツ州Wilmington)に、1000万個の細胞を皮下注射し、ノギスを使用し腫瘍体積(mm3)を11週間毎週測定した。
オープンリーディングフレームは、大文字で示す。太文字は開始コドンおよび停止コドンである。配列の更なる情報は、図1を参照せよ。
Claims (2)
- 癌を治療するための医薬の製造のための抗体またはその断片の使用であって、前記抗体が配列番号2または配列番号4のポリペプチドに結合する、使用。
- 前記癌が胃腺癌である、請求項1に記載の使用。
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US20060241284A1 (en) * | 2002-12-13 | 2006-10-26 | Juha Kuja-Panula | Transmembrane protein amigo and uses thereof |
EP2009443B1 (en) | 2006-04-18 | 2010-11-03 | Perseus Proteomics Inc. | Diagnostic agent and therapeutic agent for pancreatic cancer |
US20110097261A1 (en) * | 2006-07-20 | 2011-04-28 | Janatpour Mary J | Amigo-2-inhibitors for treating, diagnosing or detecting cancer |
JP2010280568A (ja) * | 2007-09-21 | 2010-12-16 | Perseus Proteomics Inc | 肺癌、前立腺癌、乳癌、卵巣癌、及びメラノーマの診断薬および治療剤 |
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US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US5464764A (en) | 1989-08-22 | 1995-11-07 | University Of Utah Research Foundation | Positive-negative selection methods and vectors |
WO2001053455A2 (en) * | 1999-12-23 | 2001-07-26 | Hyseq, Inc. | Novel nucleic acids and polypeptides |
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JP2003135075A (ja) * | 2001-11-05 | 2003-05-13 | Research Association For Biotechnology | 新規な全長cDNA |
US20060241284A1 (en) * | 2002-12-13 | 2006-10-26 | Juha Kuja-Panula | Transmembrane protein amigo and uses thereof |
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US20070128595A1 (en) | 2007-06-07 |
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DE60334400D1 (de) | 2010-11-11 |
EP2275573A1 (en) | 2011-01-19 |
ATE483030T1 (de) | 2010-10-15 |
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