2000 Fiscal Year Annual Research Report

炎症とがん:転写因子NF-κBによる抗アポトーシス機構と発がん促進作用

Research Project

Project/Area Number	12215128
Research Institution	Nagoya City University
Principal Investigator	岡本尚名古屋市立大学, 医学部, 教授 (40146600)
Co-Investigator(Kenkyū-buntansha)	手塚俊文名古屋市立大学, 医学部, 助手 (70322360) 河邊拓己名古屋市立大学, 医学部, 助教授 (30224843)
Keywords	発がん / NF-κB / コンプレッサー / TFIID / 53BP2 / 転写 / RelA / アポトーシス
Research Abstract	NF-κBは発がんとがんの進展に重要な役割を演じる転写因子である。我々はその主要なサブユニットであるp65(RelA)と結合する因子の包括的遺伝子スクリーニングを酵母two-hybrid screening法を用いて同定し、これらのNF-κBの生物機能の分子論的解析を進めた。その結果、今年度はp65の転写活性化ドメインに結合する因子として新たに転写コレプレッサー蛋白AES/TLE(Groucho related genes)とFUS/TLSを同定した。FUS/TLSはAES/TLEによる転写抑制を解除し、また逆にAES/TLEはFUS/TLSによるNF-κBによる転写の活性化を抑えた。FUS/TLSはTAFII蛋白のひとつと考えられており転写基本因子TFIIDの一部を構成することから、AES/TLEによるコレプレッサー作用はNF-κBの転写活性化に関わる特定のTFIIDのリクルートを排除するためと考えられた。また、p65中央部分に結合する因子として同定した53BP2のアポトーシス誘導作用とそのがん細胞株での発現の意義を明らかにし、NF-κBのアポトーシス抑制機構には遺伝子発現を必要としない経路があることを確かめた。今回我々が明らかにしたNF-κB相互作用因子の同定によるNF-κBの生物機能の解明はがん治療の標的をよりピンポイントするために有用と考えられた。今後は、NF-κBを中心とする相互作用因子の同定をさらに進めるとともに、これらの分子間相互作用の全体像を解明していき、NF-κBによる発がんとがん進展のメカニズムとその弱点を明らかにし、新たながん治療開発の基礎を確立したいと考えている。

Research Products

(14 results)

All Other

All Publications (14 results)

[Publications] Suzuki,M.: "The role of p38 mitogen-activated protein kinase in IL-6 and IL-8 production from the TNF-α or IL-1β stimulated rheumatoid synovial fibroblasts."FEBS Lett.. 465 . 23-27 (2000)
[Publications] Mori,T: "Aberrant overxpressin of 53BP2 mRNA in lung cancer cell lines."FEBS Lett.. 465. 124-128 (2000)
[Publications] Tetsuka,T.: "Inhibition of nuclear facter-κB-mediated transcription by association with the amino-terminal rnhancer of split (AES). a groucho-related protein lacking WD40 tepeats."J.Biol.Chem.. 275. 4383-4390 (2000)
[Publications] Kameoka,M.: "Evidence for Regulation of NF-κB by Poly (ADP-ribose) Polymerase."Biochem.J.. 346. 641-649 (2000)
[Publications] Kajino,S.: "Evidence that de novo protein synthesis is dispensable for anti-apoptotic effects of NF-κB."Oncogene. 19. 2233-2239 (2000)
[Publications] Kanazawa,S.: "Tat competes with C II TA for the binding to P-TEFb and blocks the exprression of MHC class II genes in HIV infection."Immunity. 12. 61-70 (2000)
[Publications] Okamoto,H.: "HIV-1 replication is inhibited by a pseudo-substrate peptide that blocks Tat transactivation."Virology. 270. 337-344 (2000)
[Publications] Kobayashi,K.: "Prevention of cancer metastasis by cimetidine through blocking the expression of E-selectin on endothelial cells."Cancer Res.. 60. 3978-3984 (2000)
[Publications] Okamoto,H.: "Inhibition of the RNA-dependent tansactivation and replication of human immunodeficiency virus type 1 by a fluoroquinoline derivative K-37."Virology. 272. 402-408 (2000)
[Publications] Nagaya,T.: "A potential role of activated NF-κB in the pathogenesis of euthyroid sick syndrome."J.Clin Invest.. 106. 393-402 (2000)
[Publications] Okamoto,H: "Reciprocal modulation of transcriptional activities between HIV-1 Tat and MHC class II transactivator C II TA. Biochem."Biophys.Res.Commun.. 279. 494-499 (2000)
[Publications] Uranishi,H.: "Involvement of the pro-oncoprotein TLS (Translocated in liposarcoma) in nuclear factor - κB p65-mediated transcription as a coactivator."J.B.C.. (in press). (2001)
[Publications] Senoo,M: "Transcriptional dysregulation of the p/3L/p63/p51/p40/KET gene, which encodes both the tumor suppressor protein p51 and its dominant-negative form p73L, in human skin cancers."Br.J.Cancer. (in press).
[Publications] Okamoto,T.: "Role of thioredoxin in the redox regulation of gene expression in inflammatory diseases."Birkhauser Verlag Basel. 13 (2000)

2000 Fiscal Year Annual Research Report

炎症とがん:転写因子NF-κBによる抗アポトーシス機構と発がん促進作用

Principal Investigator

岡本 尚 名古屋市立大学, 医学部, 教授 (40146600)

Research Products

[Publications] Suzuki,M.: "The role of p38 mitogen-activated protein kinase in IL-6 and IL-8 production from the TNF-α or IL-1β stimulated rheumatoid synovial fibroblasts."FEBS Lett.. 465 . 23-27 (2000)

[Publications] Mori,T: "Aberrant overxpressin of 53BP2 mRNA in lung cancer cell lines."FEBS Lett.. 465. 124-128 (2000)

[Publications] Tetsuka,T.: "Inhibition of nuclear facter-κB-mediated transcription by association with the amino-terminal rnhancer of split (AES). a groucho-related protein lacking WD40 tepeats."J.Biol.Chem.. 275. 4383-4390 (2000)

[Publications] Kameoka,M.: "Evidence for Regulation of NF-κB by Poly (ADP-ribose) Polymerase."Biochem.J.. 346. 641-649 (2000)

[Publications] Kajino,S.: "Evidence that de novo protein synthesis is dispensable for anti-apoptotic effects of NF-κB."Oncogene. 19. 2233-2239 (2000)

[Publications] Kanazawa,S.: "Tat competes with C II TA for the binding to P-TEFb and blocks the exprression of MHC class II genes in HIV infection."Immunity. 12. 61-70 (2000)

[Publications] Okamoto,H.: "HIV-1 replication is inhibited by a pseudo-substrate peptide that blocks Tat transactivation."Virology. 270. 337-344 (2000)

[Publications] Kobayashi,K.: "Prevention of cancer metastasis by cimetidine through blocking the expression of E-selectin on endothelial cells."Cancer Res.. 60. 3978-3984 (2000)

[Publications] Okamoto,H.: "Inhibition of the RNA-dependent tansactivation and replication of human immunodeficiency virus type 1 by a fluoroquinoline derivative K-37."Virology. 272. 402-408 (2000)

[Publications] Nagaya,T.: "A potential role of activated NF-κB in the pathogenesis of euthyroid sick syndrome."J.Clin Invest.. 106. 393-402 (2000)

[Publications] Okamoto,H: "Reciprocal modulation of transcriptional activities between HIV-1 Tat and MHC class II transactivator C II TA. Biochem."Biophys.Res.Commun.. 279. 494-499 (2000)

[Publications] Uranishi,H.: "Involvement of the pro-oncoprotein TLS (Translocated in liposarcoma) in nuclear factor - κB p65-mediated transcription as a coactivator."J.B.C.. (in press). (2001)

[Publications] Senoo,M: "Transcriptional dysregulation of the p/3L/p63/p51/p40/KET gene, which encodes both the tumor suppressor protein p51 and its dominant-negative form p73L, in human skin cancers."Br.J.Cancer. (in press).

[Publications] Okamoto,T.: "Role of thioredoxin in the redox regulation of gene expression in inflammatory diseases."Birkhauser Verlag Basel. 13 (2000)

岡本尚名古屋市立大学, 医学部, 教授 (40146600)