2003 Fiscal Year Annual Research Report

転写因子NF-κBによるアポトーシス抑制作用と発がん促進作用

Research Project

Project/Area Number	15024255
Research Institution	Nagoya City University
Principal Investigator	岡本尚名古屋市立大学, 大学院・医学研究科, 教授 (40146600)
Co-Investigator(Kenkyū-buntansha)	金澤智名古屋市立大学, 大学院・医学研究科, 助手 (90347401)
Keywords	NF-κB / p65 / ユビキチン化 / 転写活性化 / AO7 / RNA helicase A
Research Abstract	NF-κBは発がんからその進展に至る様々な段階で促進的に作用することから、がん治療の有望な標的として注目されている。実際にその阻害剤の多発性骨髄腫や腎細胞癌などでアポトーシスを誘導し、臨床での有効性が確認され、すでにFDA認可を受ける薬剤もでてきた。我々はNF-κBの作用機構を分子レベルで明らかにし、さらに分子標的を絞り込むために、NF-κBの主要サブユニットp65(RelA)との相互作用因子の遺伝子クローニングを包括的に行ってきた。昨年までに、転写のコアクチベーター活性(FUS/TLS)やコレプレッサー活性(Groucho family)を同定したが、今年度の研究よりFUS/TLSがCBPをp65にリクルートすることにより転写活性を促進することを明らかにした。また、新たにE2ユビキチンリガーゼ類似蛋白AO7とRNA helicase A(RHA)をNF-κB転写促進因子として見い出した。AO7は核内に存在し、NF-κBによる転写の活性化を促進する。AO7の中央領域に存在するRING fingerはユビキチンリガーゼ活性に必須と考えられているが、このドメインを欠失したタンパクはdominant negativeにNF-κBの作用を抑えたことからAO7はNF-κBによる転写の活性化に必須であることが明らかになった。他方、ATPase活性を欠失させたRHA変異体はdominant negativeにNF-κの作用を抑え、RNAiで内在性RHAをノックダウンすることにより種々の刺激によるNF-κB依存性転写を抑えた。以上のことより、AO7とRHAはいずれもNF-κBの転写活性に必須であることが明らかになった。

Research Products

(13 results)

All Other

All Publications (13 results)

[Publications] Jiang, X.: "The NF-κB activation in the lymphotoxin beta receptor signaling depends on the phosphorylation of p65 at serine 536."J.Biol.Chem.. 278. 919-926 (2003)
[Publications] Jiang, X.: "NF-κB p65 transacvation domain is involved in the NF-κB-inducing kinase (NIK) pathway."Biochem.Biophys.Res.Commun.. 301. 583-590 (2003)
[Publications] Matsumura, T.: "TRAF6-NF-κB pathway is essential for IL-1-induced TLR2 expression and its functional response to TLR2 ligand in murine hepatocytes."Immunology. 109. 127-136 (2003)
[Publications] Okano, A.: "Huntingtin-interacting protein-1-related protein of rat (rHIP1R) is localized in the postsynaptic regions."Brain Res.. 967. 210-225 (2003)
[Publications] Ohata, H.: "3-Methylcholanthrene activates human immunodeficiency virus type 1 replication via aryl hydrocarbon receptor."Microbiol.Immunol.. 45. 363-370 (2003)
[Publications] Teranishi, F.: "Calpain is involved in the HIV replication from the latently-infected OM10.1 cells."Biochem.Biophys.Res.Commun.. 303. 940-949 (2003)
[Publications] Asamitsu, K.: "RING finger protein AO7 supports the NF-κB-mediated transcription by interacting with the transactivation domain of p65 subunit."J.Biol.Chem.. 278. 26879-26887 (2003)
[Publications] Kanazawa, S.: "c-Myc recruitsP-TEFb for transcription, cellular proliferation and apoptosis."Oncogene. 22. 5707-5711 (2003)
[Publications] Torigoe, T.: "Low pH enhances Sp1 DNA binding activity and interaction with TBP."Nucleic Acids Res.. 31. 1-8 (2003)
[Publications] Ando, K.: "Induction of Notch signaling by tumor, necrosis factor in rheumatoid synovial fibroblasts."Oncogene. 22. 7796-7803 (2003)
[Publications] Tozawa, K.: "Gold compounds inhibit adhesion of human cancer cells to vascular endothelial cells."Cancer Lett.. 196. 93-100 (2003)
[Publications] Takahashi, N.: "Expression of 53BP2 and ASPP2 proteins from TP53BP2 gene by alternative splicing."Biochem.Biophys.Res.Commun.. 315. 434-438 (2004)
[Publications] Tetsuka, T.: "Clinical applications and novel therapeutics. Critical Reviews of Oxidative Stress and Aging."World Scientific Publishing Co.Pte.Ltd. 112-127 (2003)

2003 Fiscal Year Annual Research Report

転写因子NF-κBによるアポトーシス抑制作用と発がん促進作用

Principal Investigator

岡本 尚 名古屋市立大学, 大学院・医学研究科, 教授 (40146600)

Research Products

[Publications] Jiang, X.: "The NF-κB activation in the lymphotoxin beta receptor signaling depends on the phosphorylation of p65 at serine 536."J.Biol.Chem.. 278. 919-926 (2003)

[Publications] Jiang, X.: "NF-κB p65 transacvation domain is involved in the NF-κB-inducing kinase (NIK) pathway."Biochem.Biophys.Res.Commun.. 301. 583-590 (2003)

[Publications] Matsumura, T.: "TRAF6-NF-κB pathway is essential for IL-1-induced TLR2 expression and its functional response to TLR2 ligand in murine hepatocytes."Immunology. 109. 127-136 (2003)

[Publications] Okano, A.: "Huntingtin-interacting protein-1-related protein of rat (rHIP1R) is localized in the postsynaptic regions."Brain Res.. 967. 210-225 (2003)

[Publications] Ohata, H.: "3-Methylcholanthrene activates human immunodeficiency virus type 1 replication via aryl hydrocarbon receptor."Microbiol.Immunol.. 45. 363-370 (2003)

[Publications] Teranishi, F.: "Calpain is involved in the HIV replication from the latently-infected OM10.1 cells."Biochem.Biophys.Res.Commun.. 303. 940-949 (2003)

[Publications] Asamitsu, K.: "RING finger protein AO7 supports the NF-κB-mediated transcription by interacting with the transactivation domain of p65 subunit."J.Biol.Chem.. 278. 26879-26887 (2003)

[Publications] Kanazawa, S.: "c-Myc recruitsP-TEFb for transcription, cellular proliferation and apoptosis."Oncogene. 22. 5707-5711 (2003)

[Publications] Torigoe, T.: "Low pH enhances Sp1 DNA binding activity and interaction with TBP."Nucleic Acids Res.. 31. 1-8 (2003)

[Publications] Ando, K.: "Induction of Notch signaling by tumor, necrosis factor in rheumatoid synovial fibroblasts."Oncogene. 22. 7796-7803 (2003)

[Publications] Tozawa, K.: "Gold compounds inhibit adhesion of human cancer cells to vascular endothelial cells."Cancer Lett.. 196. 93-100 (2003)

[Publications] Takahashi, N.: "Expression of 53BP2 and ASPP2 proteins from TP53BP2 gene by alternative splicing."Biochem.Biophys.Res.Commun.. 315. 434-438 (2004)

[Publications] Tetsuka, T.: "Clinical applications and novel therapeutics. Critical Reviews of Oxidative Stress and Aging."World Scientific Publishing Co.Pte.Ltd. 112-127 (2003)

岡本尚名古屋市立大学, 大学院・医学研究科, 教授 (40146600)