2000 Fiscal Year Annual Research Report

RB経路とp53経路の相関性の解析

Research Project

Project/Area Number	12219218
Research Category	Grant-in-Aid for Scientific Research on Priority Areas (C)
Research Institution	National Cancer Center Research Institute and Research Center for Innovative Oncology, National Cancer Center Hospital East
Principal Investigator	田矢洋一国立がんセンター, 研究所・放射線研究部, 部長 (60133641)
Keywords	RB / p53 / アポトーシス / c-Myc / E2F-1 / p53AIP1
Research Abstract	1)p53はある場合にはG1停止を誘導するけれども別の場合にはアポトーシスを誘導する。この選択のメカニズムは重要な問題でありながら不明であったが、我々は、p53の新規リン酸化部位Ser46がアポトーシス誘導を制御することを見いだした。この部位は細胞のDNAが深く傷ついてアポトースが誘導される時期に一致してリン酸化が誘導される。しかも、この部位を他のアミノ酸に置換すると、p53のアポトーシス誘導能が大きく変化する。そして、p53によって発現誘導されることが知られているターゲット遺伝子のうち、東大医科学研究所の中村祐輔教授の所で単離された新規遺伝子p53AIP1の発現のみがSer46のリン酸化と一致することも見出した。p53AIP1蛋白質はミトコンドリアで働き、アポトーシスを誘導する。したがって、DNAの傷が深くて、G1停止やDNA修復が不可能になるとSer46キナーゼが活性化されて、p53のSer46がリン酸化され、p53AIP1遺伝子のプロモーターへのアフィニティーが高まり、p53AIP1が発現して細胞はアポトーシスで死ぬと考えられる。 2)Rasからのシグナルがc-Mycの安定化からE2F-1の発現誘導を通じてp53依存性のアポトーシスを誘導することがあるが、この時のc-Mycの安定化にMyc-box1に存在する2つのリン酸化部位が関係するということが以前からの研究で推定されたので、Thr58とSer62のリン酸化部位特異的抗体を作製して解析を進めた。その結果、RasからのシグナルでSer62がリン酸化されるとc-Mycの半減期が長くなって安定化し、逆に、Thr58がリン酸化されるとc-Mycの分解が促進されることがわかった。

Research Products
(16 results)

All Other

All Publications (16 results)

[Publications] Oda,K. et al.: "p53AIP1, a potential mediator of p53-dependent apoptosis, and its regulation by Ser46-phosphorylated p53."Cell. 102. 849-862 (2000)
[Publications] Seats,R. et al.: "Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability."Genes Der.. 14. 2501-2514 (2000)
[Publications] Shieh,S-Y. et al.: "The human homologues of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage inducible"Genes Der.. 14. 289-300 (2000)
[Publications] A shcroft,M. et al.: "Stress signal utilize multiple pathways to stabilize p53 : Involvement of MDM2 expression, cytoplasmic localization of p53 and ARF independent nucleolar sequestration of MDM2."Mol.Cell.Biol.. 20. 3224-3233 (2000)
[Publications] Sanchez Prieto,R. et al.: "A role for the p38 MAPK pathway in the transcriptional activation of p53 upon genotoxic stress by chemotherapeutic agents."Cancer Res.. 60. 2464-2472 (2000)
[Publications] Pandita,T. et al.: "Ionizing radiation activates the ATM kinase throughout the cell cycle."Oncogene. 19. 1386-1391 (2000)
[Publications] Kapoor,M. et al.: "Cooperative phosphorylation at multiple sites is required to activate p53 in response to UV radiation."Oncogene. 19. 358-364 (2000)
[Publications] Xiao,G. et al.: "A DNA Damage Signal Is Required for p53 to Activate gadd45."Cancer Res.. 60. 1711-1719 (2000)
[Publications] Chan,D.W. et al.: "Purification and characterization of ATM from human placenta. A manganese-dependent, workmannin-sensitive serine/threonine protein kinase."J.Biol.Chem.. 17. 7803-7810 (2000)
[Publications] Panigone,S. et al.: "pRb and cdk regulation by N-(4-hydroxyphenyl) retinamide."Oncogene. 19. 4035-4041 (2000)
[Publications] Ariumi,Y. et al.: "HTLV-1 Tax oncoprotein represses the p53-mediated transactivation function through coactivator CBP sequestration."Oncogene. 19. 1491-1499 (2000)
[Publications] Delia,D. et al.: "ATM protein and p53-serine 15 phosphorylation in ataxia telangiectasia (AT) patients and at heterozygotes."Br.J.Cancer. 82. 1938-1945 (2000)
[Publications] Nakaya,N. et al.: "Nitric oxide uses p53 to establish cell cycle arrest and induces a specific pattern of phosphorylation of p53."Oncogene. 19. 6369-6375 (2000)
[Publications] Takekawa,M. et al: "p53-inducible Wip1 phosphatasemediates a negative feedback regulation of p38 MAPK-p53 signaling in response to UV radiation."EMBO J.. 19. 6517-6526 (2000)
[Publications] Kashiwagi,M. et al.: "PKCη associates with cyclinE/cdk2/p21 complex, phosphorylates p21 and inhibits cdk2 kinase in keratinocytes."Oncogene. 19. 6334-6341 (2000)
[Publications] Gottifredi,V. et al.: "p53 accumulates but is functionally impaired when DNA synthesis is blocked."Proc.Natl.Acad.Sci.USA. 98. 1036-1041 (2001)

2000 Fiscal Year Annual Research Report

RB経路とp53経路の相関性の解析

Principal Investigator

田矢 洋一 国立がんセンター, 研究所・放射線研究部, 部長 (60133641)

Research Products

[Publications] Oda,K. et al.: "p53AIP1, a potential mediator of p53-dependent apoptosis, and its regulation by Ser46-phosphorylated p53."Cell. 102. 849-862 (2000)

[Publications] Seats,R. et al.: "Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability."Genes Der.. 14. 2501-2514 (2000)

[Publications] Shieh,S-Y. et al.: "The human homologues of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage inducible"Genes Der.. 14. 289-300 (2000)

[Publications] A shcroft,M. et al.: "Stress signal utilize multiple pathways to stabilize p53 : Involvement of MDM2 expression, cytoplasmic localization of p53 and ARF independent nucleolar sequestration of MDM2."Mol.Cell.Biol.. 20. 3224-3233 (2000)

[Publications] Sanchez Prieto,R. et al.: "A role for the p38 MAPK pathway in the transcriptional activation of p53 upon genotoxic stress by chemotherapeutic agents."Cancer Res.. 60. 2464-2472 (2000)

[Publications] Pandita,T. et al.: "Ionizing radiation activates the ATM kinase throughout the cell cycle."Oncogene. 19. 1386-1391 (2000)

[Publications] Kapoor,M. et al.: "Cooperative phosphorylation at multiple sites is required to activate p53 in response to UV radiation."Oncogene. 19. 358-364 (2000)

[Publications] Xiao,G. et al.: "A DNA Damage Signal Is Required for p53 to Activate gadd45."Cancer Res.. 60. 1711-1719 (2000)

[Publications] Chan,D.W. et al.: "Purification and characterization of ATM from human placenta. A manganese-dependent, workmannin-sensitive serine/threonine protein kinase."J.Biol.Chem.. 17. 7803-7810 (2000)

[Publications] Panigone,S. et al.: "pRb and cdk regulation by N-(4-hydroxyphenyl) retinamide."Oncogene. 19. 4035-4041 (2000)

[Publications] Ariumi,Y. et al.: "HTLV-1 Tax oncoprotein represses the p53-mediated transactivation function through coactivator CBP sequestration."Oncogene. 19. 1491-1499 (2000)

[Publications] Delia,D. et al.: "ATM protein and p53-serine 15 phosphorylation in ataxia telangiectasia (AT) patients and at heterozygotes."Br.J.Cancer. 82. 1938-1945 (2000)

[Publications] Nakaya,N. et al.: "Nitric oxide uses p53 to establish cell cycle arrest and induces a specific pattern of phosphorylation of p53."Oncogene. 19. 6369-6375 (2000)

[Publications] Takekawa,M. et al: "p53-inducible Wip1 phosphatasemediates a negative feedback regulation of p38 MAPK-p53 signaling in response to UV radiation."EMBO J.. 19. 6517-6526 (2000)

[Publications] Kashiwagi,M. et al.: "PKCη associates with cyclinE/cdk2/p21 complex, phosphorylates p21 and inhibits cdk2 kinase in keratinocytes."Oncogene. 19. 6334-6341 (2000)

[Publications] Gottifredi,V. et al.: "p53 accumulates but is functionally impaired when DNA synthesis is blocked."Proc.Natl.Acad.Sci.USA. 98. 1036-1041 (2001)

田矢洋一国立がんセンター, 研究所・放射線研究部, 部長 (60133641)