HTLV-1による細胞がん化の分子機構

• Project/Area Number: 06280103
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Research Institution: Tohoku University
• Principal Investigator: 菅村 和夫 東北大学, 医学部, 教授 (20117360)
• Co-Investigator(Kenkyū-buntansha): 渡邊 俊樹 東京大学, 医科学研究所, 助教授 (30182934) ; 内山 卓 京都大学, ウイルス研究所, 教授 (80151900) ; 藤澤 順一 (藤沢 順一) 関西医科大学, 医学部, 教授 (40181341) ; 赤城 剛 国立がんセンター研究所, ウイルス部, 研究員 (90184077) ; 藤井 雅寛 東京医科歯科大学, 医学部, 助教授 (30183099) ; 吉木 敬 北海道大学, 医学部, 教授 (60220612)
• Project Period (FY): 1994 – 1996
• Project Status: Completed (Fiscal Year 1996)
• Budget Amount: ¥108,000,000 (Direct Cost: ¥108,000,000); Fiscal Year 1996: ¥36,000,000 (Direct Cost: ¥36,000,000); Fiscal Year 1995: ¥35,000,000 (Direct Cost: ¥35,000,000); Fiscal Year 1994: ¥37,000,000 (Direct Cost: ¥37,000,000)
• Keywords: 成人T細胞白血病 / HTLV-1 / 転写活性化 / HTLV-I / HAM / 転写活性化因子 / トランスフォーメイション / ATL / Tax / トランスジェニックラット / SCIDマウス

Research Abstract

細胞の不死化およびがん化におけるHTLV-1の役割について、特にその転写活性化因子であるTaxの機能を中心に解析し、以下の研究成果が得られた。
1。Taxの新たな標的遺伝子としてSLP76を同定した。SLP76はT細胞抗原受容体を介するNFAT活性化ひいてはIL-2発現誘導に関わっている可能性が示唆された。
2。HTLV-1感染T細胞がFas誘導アポトーシスに対して抵抗性を示すことを明らかにした。この抵抗性にはTax発現とFas-associated phosphatase(FAP-1)が関わっていることが示唆された。
3。Tax変異体を用いた解析から、TaxによるT細胞増殖亢進がTaxによるNFkB活性化を介したIL-2Rα鎖の発現誘導と相関することを明らかにした。
4。TaxによるRat-1細胞トランスフォーメーションと相関して発現増強する遺伝子として、cyclophilin C-associated protein(CyCAP)を同定した。
5。HTLV-1プロウイルスTaxの一次構造多様性と転写活性化能とを調べ、40-70%のクロンにアミノ酸置換を含む塩基置換が証明された。
6。HTLV-I感染細胞と血管内皮細胞の接着分子としてOX40を同定した。ATL白血病細胞、さらにそれらの皮膚浸潤細胞にもOX40が発現することを証明した。
7。HTLV-I感染細胞に発現がみられるCD30の細胞内領域にTRAF2、TRAF5が会合し、NFkB活性化に関与していることを証明した。
HAMラットの脊髄の病理組織学的解析から、欠突起細胞のアポトーシス、TaxやTNFαの発現ならびにbcl-2の発現抑制が観察された。

Research Products

• [Publications] 竹下 敏一: "A new type of signal transducing adaptor molecule, STAM : Association with Janus kinases and involvement in cell growth and c-myc induction mediated by cytokines." Immunity. (印刷中).
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• [Publications] 東村 紀一: "Induction of OX40, a receptor of gp34, on T cells by trans-acting transcriptional activation, Tax, of human T-cell leukemia virus type I." Jpn. J. Caner Res.87. 227-231 (1996)
• [Publications] 藤井 雅寛: "Selective activation of the proto-oncogane c-jun promoter by the transforming protein of v-Rel." Oncogene. 12. 2193-2202 (1996)
• [Publications] 赤城 剛: "Expression of cell-cycle regulatory genes in HTLV-1 infected T-cells : Possible involvement of Taxl in the altered expression of cyclin D2, pI8lnk4, and p21Wafl/Cipl/SdiI." Oncogene. 12. 1645-1652 (1996)
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• [Publications] Higashimura,N.: "Indution of OX40,a receptor of gp34,on T cells by Trans-acting transcriptional activator,Tax,of human T-cell leukemia virus type I." Jpn.J.Caner Res.(in press).
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• [Publications] Akagi,T,: "Increased Protein tyrosine-Phosphorylation in primary T-cells transformed with Tax1 of human T-cell leukemia virus Type I." FEBS Lett.358. 34-38 (1995)
• [Publications] Imada,K.: "Tumorigenicity of human T-cell leukemia virus type I-infected cell lines in severe combined immunodeficient mice and characterization of the cells proliferating in vivo." Blood. 86. 2350-2357 (1995)
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• [Publications] Hirai,H.: "Tax protein of human T-cell leulemia virus type I binds to the ankyrin motifs of inhibitory factor kB and induces nuclear translocation of transcription factor NF-kB proteins for transcriptional activation." Proc.Natl.Acad.Sci.USA.91. 3584-3588 (1994)
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