JP2004196817A - 前立腺癌の治療 - Google Patents
前立腺癌の治療 Download PDFInfo
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- JP2004196817A JP2004196817A JP2004041767A JP2004041767A JP2004196817A JP 2004196817 A JP2004196817 A JP 2004196817A JP 2004041767 A JP2004041767 A JP 2004041767A JP 2004041767 A JP2004041767 A JP 2004041767A JP 2004196817 A JP2004196817 A JP 2004196817A
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Abstract
【解決手段】 例えば、配列番号:1で示されるアミノ酸配列をコードする塩基配列を含む新規なヒト遺伝子
【選択図】なし
Description
(1)GDP解離促進蛋白遺伝子のクローニング及びDNAシークエンシング
ヒト胎児脳、成人血管、胎盤の各組織より抽出したmRNAをクローンテック社より購入し、出発材料とした。
(2)ノーザンブロット分析
正常ヒト組織におけるRalGDS蛋白のmRNAの発現をランダム・オリゴヌクレオチド・プライミング法によって標識したヒトcDNAクローンをプローブとするノーザンブロットにより評価した。
(3)FISHによるコスミド・クローンと染色体の局在
FISHは、コスミド・ベクターpWE15中にクローン化されたヒト染色体のライブラリーをcDNAクローンの0.8キロ塩基挿入部をプローブとしてスクリーニングすることにより実施した(Sambrook, J., et al., Molecular Cloning, 2nd Ed., pp.3.1-3.58, Cold Spring Harbor Laboratory Press. Cold Spring Harbor, New York(1989))。
(1)細胞骨格関連蛋白2遺伝子のクローニング及びDNAシークエンシング
実施例1-(1)と同様の方法でヒト胎児脳cDNAライブラリーから任意に選択したcDNAクローンの配列解析により、ヒト細胞骨格関連蛋白遺伝子(cytoskeleton-associated protein : CAP)のCAP-グリシン領域を含有するいくつかのCAPファミリー遺伝子と相同性の高い塩基配列を有するクローンを見いだし、これをGEN-080G01と名付けた。
(2)5′レース法(5'RACE:5'rapid amplification of cDNA ends)
本発明遺伝子の5′部分を含むcDNAクローンの単離・解析は、製品使用プロトコールの一部修飾させ、市販キット(5'-Rapid AmpliFinder RACE Kit, クローンテック社)を用いた5′レース法により、以下の通り単離した。
(2)他のCRPsとCKAP2との類似性
CKAP2の配列は、レスティンとCLIP-170の配列との相同性を明らかにしたが、相同性領域は、CAP-GLYドメインの短い配列に限定されていた。アミノ酸レベルにおいて、推定されたCKAP2は、他の5つのCAPsとも高い相同性を示した。
(3)ノーザンブロット分析
正常ヒト組織におけるヒトCKAP2mRNAの発現を、実施例1-(2)と同様にしてGEN-080G01クローン(553-1015塩基に相当する)をプローブとするノーザンブロットにより評価した。
(4)ダイレクト・R-バインディングFISHによるコスミド・クローンと染色体上の局在
CKAP2cDNAに対応する2つのコスミドを得た。それらの2つのコスミド・クローンを実施例1-(3)と同様にしてダイレクト・R-バインディングFISHによってCKAP2の染色体の座位のマッピングを行なった。
(1)OTK27遺伝子のクローニング及びDNAシークエンシング
実施例1-(1)と同様の方法でヒト胎児脳cDNAライブラリーから任意に選択したcDNAクローンの配列解析とデータ・ベースの検索の結果、酵母核蛋白(Saccharomyces cerevisiae: Kolodrubetz, D. and Burgum, A., YEAST, 7, 79-90 (1991))、NHP2に対して高い相同性を有する蛋白をコードするcDNAクローン、GEN-025F07を見出し、OTK27と命名した。
(2)ノーザンブロット分析
正常ヒト組織におけるヒトOTK27mRNAの発現を、OTK27cDNAクローンのインサート部分をPCRにより増幅し、該PCR産物を精製し、〔32P〕-dCTP(ランダムプライムドDNAラベリングキット、ベーリンガーマンハイム社)により標識してプローブとし、実施例1-(2)に準じてノーザンブロッティングを行なった。
(3)ダイレクト・R-バィンディングFISHによるOKT27染色体の局在
プローブとしてOTK27cDNAのインサートを用いてcDNA OTK27に対応する1つのコスミド・クローンを全ヒト染色体コスミド・ライブラリー(5ゲノムに相当)から単離し、実施例1-(3)に準じてダイレクト・R-バィンディングFISHを実施し、OTK27の染色体の局在を決定した。
(1)OTK18遺伝子のクローニング及びDNAシークエンシング
亜鉛-フィンガー蛋白は、真核生物の転写調節を行なう蛋白の大きなファミリーと定義されており、進化的に保存された構造モチーフを含んでいる(Kadonaga, J. T., et al., Cell, 51, 1079-1090 (1987); Klung, A. and Rhodes, D., Trends Biol. Sci., 12, 464-469 (1987); Evans, R. M. and Hollenberg, S. M., Cell, 52, 1-3 (1988))。
(2)他の亜鉛フィンガー・モチーフを有する遺伝子との比較
OTK18、ヒトZNF41、ショウジョウバエのクルッペル遺伝子の比較により、各フィンガー・モチーフは、共通配列CXECGKAFXQKSXLX2HQRXHに対して大部分保存されていた。
(3)ノーザンブロット分析
ノーザンブロット分析は、実施例1-(2)に準じて、正常ヒト組織におけるヒトOTK18mRNAの発現を、OTK18cDNAクローンのインサートをPCRにより増幅し、該PCR産物を精製し、〔32P〕-dCTP(ランダムプライムドDNAラベリングキット、ベーリンガーマンハイム社)により標識してプローブとしてMTNブロットを用いて実施した。
(4)ダイレクト・R-バィンディングFISHによるコスミド・クローンと染色体の局在
OTK18の染色体の局在を実施例1-(3)に準じて行なった。
(1)ヒト26Sプロテアソーム構成成分P42蛋白質及びP27蛋白質の各遺伝子のクローニング及びDNAシークエンシング
多機能プロテアーゼであるプロテアソームは、酵母からヒトに至る真核生物に広く存在し、細胞内でエネルギー依存的にユビキチン結合蛋白質を分解する酵素である。該プロテアソームは、構造的には分子量21〜31キロダルトンの種々の構成成分からなる20Sプロテアソームと、30〜112キロダルトンの種々の構成成分からなる沈降係数22SのPA700制御蛋白質群とで構成され、全体として沈降係数26S、分子量約200万ダルトンの巨大分子を形成している〔Rechsteiner, M., et al., J.Biol.Chem., 268, 6065-6068 (1993)、Yoshimura, T., et al., J.Struct.Biol., 111, 200-211 (1993)、Tanaka, K., et al., New Biologist, 4, 173-187 (1992)〕。
(1)ヒト26Sプロテアソーム構成成分P42蛋白質及びP27蛋白質の精製
新鮮なヒト腎臓約100gを用い、特開平5-292964号公報に記載されているヒトプロテアソームの精製法に従い、バイオゲルA-1.5m(5×90cm、バイオラッド製)、ハイドロキシアパタイト(1.5×15cm、バイオラッド製)、Q-セファロース(1.5×15cm、ファルマシア製)によるカラムクロマトグラフィー及びグリセロール密度勾配遠心法により、ヒトプロテアソームの精製を行なった。
第1液:0.06%トリフルオロ酢酸
第2液:0.05%トリフルオロ酢酸、70%アセトニトリル
各溶出画分につき、その一部をジチオスレイトール還元下、8.5%SDS-ポリアクリルアミド電気泳動を行ない検出し、P42蛋白質及びP27蛋白質をそれぞれ単離精製した。
本発明者らは、実施例1-(1)に示すように、ヒト胎児脳、血管動脈、胎盤cDNAライブラリーの大量DNA配列の決定から、約3万個のcDNAデーターを含むデーターベースを構築している。
(1)BNAP遺伝子のクローニング及びDNAシークエンシング
DNAとヒストンで構成されるヌクレオソームは、真核生物の細胞において染色体を構成する基本構造で、種を越えてよく保存されている。この構造は、DNAの複製過程と転写に強く関連している。しかしながら、ヌクレオソームの形成については、完全には理解されておらず、ヌクレオソーム構築(nucleosome assembly: NAPs)に係わるいくつかの特異的な因子が確認されているのみである。即ち、既に2つの酸性蛋白であるヌクレオプラスミン(nucleoplasmin)とN1が、ヌクレオソーム構築を容易にすることが確認されている(Kleinschmidt, J.A., et al., J. Biol. Chem., 260, 1166-1176 (1985): Dilworth, S. M., et al., Cell, 51, 1009-1018 (1987))。
(2)BNAPとNAPsとの比較
BNAPの推定アミノ酸配列は、hNRPと46%の同一性と65%の類似性を示した。
(3)ノーザンブロット分析
ノーザンブロット分析は、実施例1-(2)に準じて、正常ヒト組織におけるBNAPmRNAの発現を、クローンGEN-078D05TA13(BNAP遺伝子の配列番号323から1558番目に相当する)をPCRにより増幅し、該PCR産物を精製し、[32P]-dCTP(ランダムプライムドDNAラベリングキット、ベーリンガーマンハイム社)により標識し、プローブとしてMTNブロットに用いて試験した。
(4)ラディエーション・ハイブリッド・マッピング(Radiation Hybrid Mapping)
ラディエーション・ハイブリッド・マッピングによって、BNAPのクローンの染色体マッピングを行なった(Cox, D.R., et al., Science, 250, 245-250 (1990))。
ユビキチン・システムは、細胞プロセスに必須の酵素グループのひとつであり、酵母からヒトにいたるまで保存されている。該システムは、ユビキチン活性酵素(ubiquitin-activating enzymes: UBAs)、ユビキチン結合酵素(ubiquitin-conjugating enzymes: UBCs)、ユビキチン蛋白リガーゼ(ubiquitin protein ligases: UBRs)及び26Sプロテアソーム粒子から構成されている。
(1)ヒト骨格筋特異的ユビキチン結合酵素遺伝子(UBE2G遺伝子)のクローニング及びDNAシークエンシング
実施例1-(1)と同様の方法でヒト胎児脳cDNAライブラリーから任意に選択したcDNAクローンの配列解析とデータ・ベースの検索の結果、GEN-423A12cDNAクローンが様々な種のユビキチン結合酵素(ubiquitin-conjugating enzymes: UBCs)をコードする遺伝子と有意に高い相同性を有する持つことが分かった。
(b)AGGATGAの配列は、開始コドン周辺のコンセンサス配列(A/G)CCATGG(Kozak, M., J. Biol. Chem., 266, 19867-19870 (1991))に類似していた。
(2)UBE2GとUBCsとのアミノ酸配列との比較
UBE2GとUBCsとのアミノ酸配列の比較から、ユビキチンに結合することができる活性部位システィンは、90番目のシスティン残基であるように思えた。これらの遺伝子でコードされるペプチドは、同じファミリーに属しているようである。
(3)ノーザンブロット分析
ノーザンブロット分析は、実施例1-(2)に準じて、正常ヒト組織におけるUBE2GmRNAの発現を、UBE2Gの全配列をPCRにより増幅し、該PCR産物を精製し、[32P]-dCTP(ランダムプライムドDNAラベリングキット、ベーリンガーマンハイム社)により標識し、プローブとして用い、メンブレンは、MTNブロットを用いて実施した。
(4)ラディエーション・ハイブリッド・マッピング(Radiation Hybrid Mapping)
ラディエーション・ハイブリッド・マッピングによって前記実施例6-(4)と同様の方法でUBE2Gのクローンの染色体マッピングを行なった。
(1)TMP-2遺伝子のクローニング及びDNAシークエンシング
実施例1-(1)と同様の方法でヒト胎児脳cDNAライブラリーから任意に選択したcDNAクローンの配列解析とデータ・ベースの検索の結果、膜蛋白遺伝子(transmembrane protein:アクセッションNo.;U19878)に相同性の高いcDNA配列を有するクローン(GEN-092E10)を見出した。
(2)ノーザンブロット分析
ノーザンブロット分析は、実施例1-(2)に準じて、正常ヒト組織におけるTMP-2mRNAの発現を、クローンGEN-092E10をPCRにより増幅し、該PCR産物を精製し、[32P]-dCTP(ランダムプライムドDNAラベリングキット、ベーリンガーマンハイム社)により標識し、プローブとしてMTNブロットを用いて実施した。
(1)ヒトNPIK遺伝子のクローニング及びDNAシークエンシング
実施例1及び2と同様の方法で、ヒト胎児脳cDNAライブラリーから任意に選択したcDNAクローンの配列解析とデータ・ベースの検索の結果、フォスファチジルイノシトール(phosphatidylinositol)3及び4キナーゼに保存されているアミノ酸配列をコードする遺伝子(Kunz, J., et al., Cell, 73, 585-596 (1993))に高い相同性を有する2つのcDNAクローンを得、これらをGEN-428B12c1及びGEN-428B12c2と命名し、これらの全配列を、前記各実施例に準じて決定した。
(2)ノーザンブロット分析
ノーザンブロット分析は、実施例1-(2)に準じて、正常ヒト組織におけるヒトNPIKmRNAの発現を、ヒトNPIKの全配列をPCRにより増幅し、該PCR産物を精製し、[32P]-dCTP(ランダムプライムドDNAラベリングキット、ベーリンガーマンハイム社)により標識し、プローブとして用い、メンブレンは、MTNブロットを用いて実施した。
(1)NRP1遺伝子及びNRP2遺伝子のクローニング及びDNAシークエンシング
EGF様反復配列は、多くの膜蛋白質において確認されており、成長調節と分化に関連する蛋白中において確認されている。このモチーフは蛋白間相互作用に関係しているように思われている。
(2)ノーザンブロット分析
ノーザンブロット分析は、実施例1-(2)に準じて、正常ヒト組織におけるNRPsmRNAの発現を、両クローンしたcDNAsの全体の配列をPCRにより増幅し、該PCR産物を精製し、[32P]-dCTP(ランダムプライムドDNAラベリングキット、ベーリンガーマンハイム社)により標識し、2つのプローブとしてMTNブロットに用いて実施した。
(3)FISHによるNRP1遺伝子及びNRP2遺伝子の染色体のマッピング
実施例1-(3)に準じてFISHによるNRP1遺伝子及びNRP2遺伝子の染色体のマッピングを行なった。
(1)GSPT1-TK遺伝子のクローニング及びDNAシークエンシング
ヒトGSPT1遺伝子は、細胞サイクルのG1期からS期転位に重要なGTP結合蛋白をコードする酵母のGST1遺伝子のヒト相同遺伝子のひとつである。サッカロミセス・セレビシェ(Saccharomyces cerevisiae)の温度感受性gst1(G1-to-S転位)変異体を補って完全にすることができる蛋白として、最初に特定された酵母のGST1遺伝子は、酵母の染色体ライブラリーから単離された(Kikuchi,Y., Shimatake, H. and Kikuchi, A., EMBO J. 7, 1175-1182 (1988))、該遺伝子は、cAMP依存性蛋白キナーゼの標的部位とGTPaseドメインを持つ蛋白をコードしていた。
(2)ノーザンブロット分析
ノーザンブロット分析は、実施例1- (2)に準じて、正常ヒト組織におけるGSPT1-TKmRNAの発現を、GEN-077A09cDNAクローンをPCRにより増幅し、該PCR産物を精製し、[32P]-dCTP(ランダムプライムドDNAラベリングキット、ベーリンガーマンハイム社)により標識し、プローブとしてMTNブロットに用いて実施した。
(3)FISHによるGSPT1-TK遺伝子の染色体のマッピング
実施例1-(3)に準じてFISHによるGSPT1-TK遺伝子の染色体のマッピングを行なった。
Claims (4)
- ヒトTMP-2蛋白質に対する抗体を含む製剤学的組成物を処置を要求される患者に投与することを特徴とする前立腺癌の治療方法。
- ヒトTMP-2蛋白質に対する抗体が、治療剤部分と結合される請求項1に記載の方法。
- 治療剤部分が、細胞傷害性薬剤である請求項2に記載の方法。
- 治療剤部分が、ラジオアイソトープである請求項2に記載の方法。
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