JP2000513927A - レチノイド代謝蛋白質 - Google Patents
レチノイド代謝蛋白質Info
- Publication number
- JP2000513927A JP2000513927A JP10502007A JP50200798A JP2000513927A JP 2000513927 A JP2000513927 A JP 2000513927A JP 10502007 A JP10502007 A JP 10502007A JP 50200798 A JP50200798 A JP 50200798A JP 2000513927 A JP2000513927 A JP 2000513927A
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- seq
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- dna
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- C12N9/0004—Oxidoreductases (1.)
- C12N9/0071—Oxidoreductases (1.) acting on paired donors with incorporation of molecular oxygen (1.14)
- C12N9/0077—Oxidoreductases (1.) acting on paired donors with incorporation of molecular oxygen (1.14) with a reduced iron-sulfur protein as one donor (1.14.15)
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- A—HUMAN NECESSITIES
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Abstract
Description
Claims (1)
- 【特許請求の範囲】 1.レチノイドを酸化する能力を有し、配列番号:2、配列番号:4、もしくは 配列番号32:として同定されたアミノ酸配列、またはその機能的に同等な相同体 と比較して、少なくとも約30%保存されているアミノ酸配列を有する精製蛋白質 。 2.配列番号:2、配列番号:4、もしくは配列番号:32として同定されたアミ ノ酸配列、またはその機能的に同等な相同体と比較して、少なくとも約35%保存 されている、請求項1記載の蛋白質。 3.配列番号:2、配列番号:4、もしくは配列番号:32として同定されたアミ ノ酸配列、またはその機能的に同等な相同体と比較して、少なくとも約50%保存 されている、請求項1記載の蛋白質。 4.請求項1記載の蛋白質、またはその保存的置換された変異体。 5.レチノイドがレチノールおよび/またはレチノイン酸である、請求項1記載 の蛋白質。 6.レチノイドのβ-イオノン環の4位の炭素を酸化する能力を有する、請求項 1記載の蛋白質。 7.レチノイドが全トランス型レチノイドである、請求項6記載の蛋白質。 8.レチノイン酸のβ-イオノン環の4位でレチノイン酸をヒドロキシル化する 能力を有し、配列番号:2、配列番号:4、もしくは配列番:32として同定され たアミノ酸配列、またはその機能的に同等な相同体と比較して、少なくとも約30 %保存されているアミノ酸配列を有する精製蛋白質。 9.レチノイドのβ-イオノン環の4位の炭素においてレチノイドを酸化する能 力を有する精製蛋白質。 10.レチノイドが全トランス型レチノイドである、請求項9記載の蛋白質。 11.レチノイドがレチノイン酸である、請求項10記載の蛋白質。 12.請求項1記載の蛋白質またはその保存的置換された変異体。 13.請求項1記載の蛋白質をコードする単離された核酸分子、またはストリンジ ェントなハイブリダイゼーション条件下で該核酸分子とハイブリダイズすること が可能な核酸鎖。 14.請求項8記載の蛋白質をコードする単離された核酸分子。 15.配列番号:3、配列番号:5、もしくは配列番号:31として同定された配列 を有するDNA分子を含む、もしくは遺伝子コードの縮重により該配列と異なる単 離された核酸分子、またはストリンジェントなハイブリダイゼーション条件下で 該核酸分子の少なくとも1つとハイブリダイズすることが可能な核酸鎖。 16.核酸分子の配列が、ヒトゲノム、魚ゲノム、もしくはマウスゲノムの一部に 対応する、または遺伝子コードの縮重によりそれとは異なる、請求項15記載の核 酸分子。 17.請求項15記載の核酸分子に対応する配列を有するDNAから転写された単離mRN A。 18.レチノイド誘導可能蛋白質をコードする異種DNAを含みかつ発現させる微生 物細胞。 19.蛋白質がレチノイドを酸化することができる、請求項18記載の微生物細胞。 20.全トランス型レチノイン酸4-ヒドロキシラーゼ活性を有するレチノイド誘導 可能蛋白質をコードする異種DNAを含みかつ発現させる微生物細胞。 21.レチノイドがレチノイン酸である、請求項18記載の細胞。 22.請求項13記載の核酸分子と相補的な異種DNAを含みかつ発現させる微生物細 胞。 23.組換え型クローニングベクターにおいて請求項15記載の配列を有する単離さ れたDNA。 24.請求項1記載の蛋白質を発現する安定的にトランスフェクトされた細胞系。 25.請求項15記載の核酸配列を有する組換えDNA分子で形質転換された細胞培養 物。 26.請求項1記載の蛋白質を産生するよう遺伝的に改変された宿主細胞であって 、該蛋白質をコードする異種DNAをその中で発現するよう組み込まれた細胞。 27.細胞をレチノイン酸に暴露することによって蛋白質の産生を誘導することが できる、請求項26記載の細胞。 28.真核細胞である、請求項26記載の細胞。 29.下記の段階を含む、請求項1記載の蛋白質を製造するための方法: 該蛋白質をコードするヌクレオチド配列を含むDNA断片を調製する段階、 該DNA断片を含み、かつ複製されうる組換えDNA分子を得るために発現ベクター に該DNA断片を組み込む段階、 該蛋白質を発現させることのできる形質転換体を製造するために該組換えDNA 分子で宿主細胞を形質転換させる段階、 該蛋白質を製造するために該形質転換体を培養する段階、および その結果生じた培養混合物から該蛋白質を回収する段階。 30.請求項1記載の蛋白質に対する抗体。 31.モノクローナル抗体である、請求項30記載の抗体。 32.配列番号:4と同定された配列に含まれる1つの配列を有する蛋白質に対す る抗体。 33.レチノイン酸の代謝を必要とする生物または細胞において該代謝に用いられ る請求項1記載の蛋白質。 34.請求項1記載の蛋白質を投与することを含む、レチノイン酸代謝を必要とす る生物または細胞においてレチノイン酸を代謝させる方法。 35.配列番号:3、配列番号:5、または配列番号:31と同定された配列の少な くとも一部と実質的に相補的なアンチセンス核酸またはオリゴヌクレオチドの有 効量を生物に投与することを含む、レチノイン酸ヒドロキシル化の阻害を必要と する生物においてそれを阻害する方法。 36.その一部の長さが少なくとも5塩基である、請求項35記載の方法。 37.生物がヒトである、請求項35記載の方法。 38.生物を、癌、紫外線角化症、口腔白板症、頭部および/または頸部の二次腫 瘍、肺の非小細胞癌、基底細胞癌、急性前骨髄性白血病、皮膚癌、ならびに紫外 線角化症、ざ瘡、乾癬、および/または魚鱗癬に関連する前悪性腫瘍からなる群 より選択される疾患に関して治療する、請求項35記載の方法。 39.疾患が急性前骨髄性白血病である、請求項38記載の方法。 40.下記の段階を含む、所望の蛋白質を製造するための方法: レチノイドへの暴露に反応して内因性蛋白質を産生することのできる細胞を提 供する段階、 内因性蛋白質をコードするDNA配列が通常存在する部位またはその近傍に所望 の蛋白質をコードするDNA配列を細胞のDNAに組み込む段階、および 該所望の蛋白質の産生を誘導するため、レチノイドに該細胞を暴露する段階。 41.規定量の蛋白質と抗体とが結合すると、リポーターシステムが検出可能な反 応を生じる、リポーターシステムに結合した該蛋白質に対する抗体を含む、請求 項1記載の蛋白質、または配列番号:4と同定されるアミノ酸配列を有する蛋白 質の有無を判定するキット。 42.請求項13記載の第一の核酸分子の有無を判定するキットであって、規定量の 第一の分子と第二の分子とを共にハイブリダイズさせると検出可能な反応を生じ るリポーターシステムに第二の核酸分子が結合している、ストリンジェントな条 件下で第一の核酸分子の少なくとも一部とハイブリダイズすることができる第二 の核酸分子を含む、キット。 43.核酸分子の長さが少なくとも約5塩基である、請求項42記載のキット。 44.(a)配列番号:33; (b)配列番号:34; (c)配列番号:35;および (d) (a)、(b)、または(c)の断片 からなる群より選択されるヌクレオチド配列を有する単離されたDNA分子であっ て、プロモーター活性を有するDNA分子。 45.xが5までの値である配列TGAACT(N)xTGAACTを含む、請求項44記載のDNA分子 。 46.xが5である請求項45記載のDNA分子。 47.配列TGAACT(N)xTGAACTの下流に配列TCTGASSAAGKTAACをさらに含む、請求項4 5記載のDNA分子。 48.配列TGAACT(N)xTGAACTと配列TCTGASSAAGKTAACとの間に配列AATTをさらに含 む、請求項47記載のDNA分子。 49.配列TGAACT(N)xTGAACTと配列TCTGASSAAGKTAACとの間に6個までのヌクレオ チドが存在する、請求項48記載のDNA分子。 50.配列TGAACT(N)xTGAACTの上流に配列CAATTAAAGAをさらに含む、請求項45記載 の DNA分子。 51.配列CAATTAAAGATGAACTTTGGGTGAACTAATTを含む、請求項44記載のDNA分子。 52.配列TATAAを含む請求項44、45、46、47、48、49、50、または51記載のDNA分 子。 53.配列TGAACT(N)xTGAACTの下流に配列TATAAを含む、請求項45、46、または50 記載のDNA分子。 54.配列TCTGASSAAGKTAACの下流に配列TATAAを含む、請求項47または48記載のDN A分子。 55.配列TGAACT(N)xTGAACTの下流に、そこから最大で約55ヌクレオチドの間隔を あけて位置する配列TATAAを含む、請求項45記載のDNA分子。 56.請求項44記載の単離DNA分子を含む組換えDNA。 57.1つ以上の構造遺伝子をさらに含む、請求項51記載の組換えDNA。 58.1つ以上の構造遺伝子がチトクロームP450蛋白質をコードする、請求項56記 載の組換えDNA。 59.請求項56記載の組換えDNAを含む発現プラスミド。 60.請求項57記載の組換えDNAを含む単離された細胞。 61.真核細胞である、請求項56記載の単離された細胞。 62.請求項60記載の細胞を培養し、産生された蛋白質を回収する段階を含む、組 換え蛋白質を製造するための方法。 63.蛋白質がチトクロームP450を含む、請求項62記載の方法。 64.蛋白質が融合蛋白質を含む、請求項62記載の方法。 65.レチノイン酸誘導可能蛋白質の活性に及ぼす作用について薬物をスクリーニ ングする方法であって、該薬物に精製された該蛋白質を暴露し、該活性に及ぼす 作用を測定する段階を含む、方法。 66.活性が、レチノイン酸、特に全トランス型レチノイン酸のヒドロキシル化で ある、請求項65記載の方法。 67.請求項1記載の蛋白質の活性に及ぼす作用について薬物をスクリーニングす る方法であって、該薬物に精製された該蛋白質を暴露し、該活性に及ぼす作用を 測定する段階を含む、方法。 68.レチノイン酸の酸化に対する薬物の作用を確認する段階を含む、請求項67記 載の方法。 69.レチノイドが全トランス型レチノイン酸である、請求項68記載の方法。 70.レチノイドによって誘導可能である遺伝子の発現に及ぼす作用について薬物 をスクリーニングする方法であって、該薬物に請求項60記載の組換えDNAを暴露 し、遺伝子発現に及ぼす作用を測定する段階を含む、方法。 71.レチノイドの存在下で組換えDNAを暴露する段階を含む、請求項70記載の方 法。 72.構造遺伝子がレチノイン酸を代謝しないリポーター遺伝子である、請求項70 記載の方法。 73.遺伝子発現に及ぼす作用を測定する段階に、遺伝子の転写に及ぼす作用を確 認する段階が含まれる、請求項70記載の方法。 74.請求項1記載の、発現系に組み込まれるヌクレオチド配列によってコードさ れるチトクロームP450の本来のプロモーター活性を有するヌクレオチド配列の調 節下となるように、該チトクロームP450によるレチノイドの代謝に及ぼす作用に ついて薬物をスクリーニングする方法であって、レチノイドの代謝に及ぼす薬物 の作用を測定するためにレチノイドの存在下で薬物に該系を暴露する段階を含む 、方法。 75.レチノイドがレチノイン酸である、請求項74記載の方法。 76.レチノイン酸が全トランス型レチノイン酸である、請求項74または75記載の 方法。 77.請求項65、66、67、68または69記載の方法により、蛋白質の活性を調節する 作用を有すると同定された薬物。 78.請求項70、71、72、73、74または75記載の方法により、遺伝子発現を調節す る作用を有すると同定された薬物。 79.請求項76記載の方法により、遺伝子発現を調節する作用を有すると同定され た薬物。 80.請求項77記載の薬物の有効量を生物に投与する段階を含む、レチノイン酸代 謝の阻害を必要とする生物において該代謝を阻害する方法。 81.請求項78記載の薬物の有効量を生物に投与する段階を含む、レチノイン酸代 謝の阻害を必要とする生物において該代謝を阻害する方法。 82.請求項79記載の薬物の有効量を生物に投与する段階を含む、レチノイン酸代 謝の阻害を必要とする生物において該代謝を阻害する方法。
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US08/724,466 US6063606A (en) | 1996-06-21 | 1996-10-01 | Retinoid metabolizing protein |
PCT/CA1997/000440 WO1997049815A1 (en) | 1996-06-21 | 1997-06-23 | Retinoid metabolizing protein |
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US7115558B2 (en) | 1999-12-16 | 2006-10-03 | Cytochroma Inc. | P450RAI-2(P450 Cytochrome 26B), encoding nucleic acid molecules and methods and uses thereof |
WO2002048334A2 (en) * | 2000-12-15 | 2002-06-20 | Cytochroma Inc. | P450rai-2 (p450 cytochrome 26b), encoding nucleic acid molecules and methods and uses thereof |
US7537919B2 (en) | 1999-12-16 | 2009-05-26 | Cytochroma Inc. | Cytochrome P450RAI-2 and related proteins |
US6444222B1 (en) * | 2001-05-08 | 2002-09-03 | Verigen Transplantation Services International Ag | Reinforced matrices |
CA2448933C (en) | 2001-05-23 | 2012-05-15 | Cytochroma Inc. | A retinoic acid metabolizing cytochrome p450 |
CA2456210A1 (en) * | 2001-08-03 | 2003-06-26 | Diversa Corporation | P450 enzymes, nucleic acids encoding them and methods of making and using them |
US7288407B2 (en) | 2002-05-02 | 2007-10-30 | Cytochroma, Inc. | Stable cytochrome P450 24 (CYP24) expressing cell line and methods and uses thereof |
US7427670B2 (en) | 2003-12-19 | 2008-09-23 | Cytochroma Inc. | Cytochrome P450 24 (CYP24) monoclonal antibody and methods and uses thereof |
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US6306624B1 (en) | 2001-10-23 |
ATE309370T1 (de) | 2005-11-15 |
AU3162097A (en) | 1998-01-14 |
EP0935676A2 (en) | 1999-08-18 |
EP0910644A1 (en) | 1999-04-28 |
JP4283342B2 (ja) | 2009-06-24 |
JP2000513928A (ja) | 2000-10-24 |
DE69734586T2 (de) | 2006-08-10 |
CA2257180A1 (en) | 1997-12-31 |
CA2257352C (en) | 2011-11-29 |
EP0910644B1 (en) | 2005-11-09 |
WO1997049815A1 (en) | 1997-12-31 |
AU3332197A (en) | 1998-01-14 |
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WO1997049832A2 (en) | 1997-12-31 |
IN186424B (ja) | 2001-09-01 |
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