HTLV-1による遺伝子発現と細胞増殖の脱制御の研究

• Project/Area Number: 06283205
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas (A)
• Allocation Type: Single-year Grants
• Research Institution: The University of Tokyo
• Principal Investigator: 吉田 光昭 東京大学, 医科学研究所, 教授 (80012607)
• Co-Investigator(Kenkyū-buntansha): 鈴木 健之 東京大学, 医科学研究所, 助手 (30262075) ; 平井 洋 東京大学, 医科学研究所, 助手 (10202277) ; 松崎 洋一郎 東京大学, 医科学研究所, 教務職員 (70282522) ; 谷村 朗 東京大学, 医科学研究所, 助手 (90251446)
• Project Period (FY): 1998
• Project Status: Completed (Fiscal Year 1998)
• Budget Amount: ¥169,000,000 (Direct Cost: ¥169,000,000); Fiscal Year 1998: ¥35,000,000 (Direct Cost: ¥35,000,000); Fiscal Year 1997: ¥39,000,000 (Direct Cost: ¥39,000,000); Fiscal Year 1996: ¥35,000,000 (Direct Cost: ¥35,000,000); Fiscal Year 1995: ¥30,000,000 (Direct Cost: ¥30,000,000); Fiscal Year 1994: ¥30,000,000 (Direct Cost: ¥30,000,000)
• Keywords: 細胞周期 / 細胞周期阻害因子 / 成人T細胞白血病 / 転写因子 / 遺伝子発現 / ウイルス発がん / HTLV-1 / 転写活性化 / 白血病ウイルス / 白血病

Research Abstract

ヒトレトロウイルス(HTLV-1)による成人T細胞白血病(ATL)の発症機構の解明を目的にして、そのがん原性蛋白Taxの機能についてさらに検討した。
昨年度までの研究で、HTLV-1の制御因子Taxは転写活性化因子であり、CREB、NF-κB、IkB、SRFへの結合によって多くの遺伝子発現を亢進する一方、細胞周期の阻害因子p16ink4Aに結合して、Cdk4キナーゼを活性化を誘導して、RBの不活化を介してG1期に停止した細胞の増殖を促進することも見出した。DNAウイルスのがん原性蛋白もRBを不活化してがんを起こすことから、Taxと16の相互作用がATLの発症に重要な役割を果たすことを示唆した。
今年度は、p16ink4Aのファミリーであるp18ink4C遺伝子の転写が、Taxにより抑制される機構を解析した。その結果、p18ink4C遺伝子の転写抑制にはE-BoxにE47が結合し、それにp300の会合がかかわること、p53依存性の転写の抑制にはp53とCBPが関わることを見出した。さらにこの抑制系でTaxがCBP/p300に結合して、CBP/p300のDNAへの会合を阻害していることを示した。これらのことから、TaxはCBP/p300に結合し、この複合体中のTaxがDNA結合蛋白に親和性がないときには転写を阻害し、親和性の強いときには転写を活性化するという、転写の活性化と抑制の統一的機構を提唱した。CBP/p300は極めて多くの遺伝子発現に関わるので、Taxの転写制御に関わるカスケードは予想より大きいものであると予想された。

Research Products

• [Publications] Inoue,M,Yoshida,M 他: "Characterization of mRNA expression of IkBa and NF-kB subfamilies in primary adult T-cell leukemia cells." Jpn.J.Cancer Res.89. 53-59 (1998)
• [Publications] Kishimoto,T,Yoshida,M 他: "Enhanced expression of a new class of liver-enriched b-zip transcription factors,hepatocarcinogenesis-related transcription factor,in hepatocellular carcinomas" Cell Growth & Differentiation. 9. 337-344 (1998)
• [Publications] Miyake,H,Yoshida,M 他: "Trans-activator Tax of human T-cell leukemia virus type 1(HTLV-1) enhances mutation frequency of the cellular genome." Virology. 253. 155-161 (1999)
• [Publications] Dan,S,Yoshida,M 他: "Interaction of Gli2 with CREB protein on DNA elements in long terminal repeat of human T cell leukemia virus type 1(HTLV-1) responsible for transcriptional" J.Virol.(in press).
• [Publications] Suzuki,T,Yoshida,M 他: "Tax protein of HTLV-1 inhibits CBP/p300-mediated transcription by interfering with recruitment of CBP/p300 onto DNA element of E-box or p53 binding site." Oncogene. (in press).
• [Publications] Tanimura,A: "Cloning of novel isoforms of human Gli2 oncogene and their activities to enhance Tax-dependent transcription of HTLV-1 genome." J.Virol.(in press).
• [Publications] Inoue,M: "Characterization of mRNA expression of IκBα and NF-κB subfamilies in primary adult T-cell leukemia cells." Jpn.J.Cancer Res.89. 53-59 (1998)
• [Publications] Yoshida,M: "Molecular biology of HTLV-1 : Deregulation of host cell gene expression and cell cycle." Leukemia. 11. 14-15 (1997)
• [Publications] Suzuki,T: "HTLV-1 Tax protein interacts with cyclin-dependent kinase inhibitor p16^<INKGA> and counteracts its inhibitory activity towards CDK4" The EMBO J.15. 1607-1614 (1996)
• [Publications] Yamagata,T: "A novel interferon regulatory factor family transcription factor,ICSAT/Pip/LSIRF,that negatively regulates the activity of interferon-regulated genes" Mol.Cell.Biol.16. 1283-1294 (1996)
• [Publications] Saito,M: "Mutation rates in LTR Of HTLV-1 in HAM/TSP patients and the carriers are similarly high to Tax/Rex-coding sequence" J.Neuro Virol.2. 330-335 (1996)
• [Publications] Yoshida,M: "Molecular biology of HTLV-1:Recent progress" Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology. 13. S63-S68 (1996)
• [Publications] Yoshida,M: "Molecular biology of HTLV-1:Dereguration of host cell gene expression and cell cycle" Leukemia. (in press). (1996)
• [Publications] Yoshida,M: "Multiple targets of HTLV-1 for dysregulation of host cells" Seminars in Virology. 7. 349-360 (1996)
• [Publications] Yoshida,M: "Human c-type oncoviruses and T cell leukemia/lymphoma In “Microbes and Malignancy:Infection as a cause of cancer"" (in press), (1996)
• [Publications] Murakami,T: "HTLV-1 Tax enhances NF-kB2 expression and binds to the products p52 and p100,but does not suppress the inhibitory function of p100" Virology. 206. 1066-1074 (1995)
• [Publications] Matsuzaki,Y: "Identification of transcriptional activation domain of TREB5,a CREB1 ATF family protein,that binds to HTLV-1 enhancer" J.Biochem:. 117. 303-308 (1995)
• [Publications] Furukawa,Y: "HTLV-1 Tax is expressed at the same level in infected cells of HAM/TSP patients as in asymptomatic carriers but at a lower level in ATL patients" Blood. 85. 1865-1870 (1995)
• [Publications] Suzuki,T: "HTLV-1 Tax protein interacts with cyclin-dependent kinase inhibitor p16 INK4A and counteracts its inhibitory activity to CDK4" The EMBO Journal. (in press). (1996)
• [Publications] Suzuki,T: "Tax protein of HTLV-1 destabilizes the complexes of NF-kB and IkB-α and induces nuclear translocation of NF-kB for transcriptional activation" Oncogene. 10. 1199-1207 (1995)
• [Publications] Saito,M: "Frequent mutation in pX region of HTLV-1 is observed in HAM/TSP patients,but is not specifically associated with the central nervous system lesions" Journal of Neuro Virology. 1. 286-294 (1995)
• [Publications] Suzuki,T.: "Tax protein of HTLV-1 destabilizes the complexes of NF-κB and IkB-α and induces nuclear translocation of NF-κB for transcriptional activation." Oncogene. (in press). (1995)
• [Publications] Furukawa,Y.: "HTLV-1 Tax is expressed at the same level in infected cells of HAM/TSP patiense as in asymptomatic carriers but at a lower level in ATL patient." Blood. (in press). (1995)
• [Publications] Murakami,T.: "HTLV-1 Tax enhances NF-κB2 expression and binds to the products p52 and p100,but does not suppress the inhibitory function of p100." Virology. (in press). (1995)
• [Publications] Suzuki,T.: "Tax protein of HTLV-1 interacts with the Rel homology domain of NF-κB p65 and c-Rel proteins bound to the NF-κB binding site and activates transcription." Oncogene. 9. 3099-3105 (1994)
• [Publications] Hirai,H.: "Tax protein of human T-cell leukemiu virus typeI binds to the ankyrin motifs of inhibitory factor κB and induces nuclear translocation of transcriprion factor NF-κB proteins for transcriptional activation." Proceedings of the National Academy of Science. 91. 3584-3588 (1994)
• [Publications] Miura,T.: "Phylogenetic subtypes of human T-cell lymphotropic virus type I and their relations to the anrhropological background." Proceedings of the National Academy of Science. 91. 1124-1127 (1994)