生体防御と癌化を制御する遺伝子群の研究

• Project/Area Number: 06283217
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas (A)
• Allocation Type: Single-year Grants
• Research Institution: The University of Tokyo (1995-1999); Osaka University (1994)
• Principal Investigator: 谷口 維紹 東京大学, 大学院・医学系研究科, 教授 (50133616)
• Co-Investigator(Kenkyū-buntansha): 田中 信之 東京大学, 大学院・医学系研究科, 助教授 (80222115) ; 宮崎 忠昭 東京大学, 医学部, 助手 (60272431) ; 瀧 伸介 東京大学, 医学部, 講師 (50262027) ; 原田 久士 東京大学, 医学部(医), 助手 (10222233) ; 南 康博 大阪大学, 細胞生体工学センター, 助手 (70229772)
• Project Period (FY): 1999
• Project Status: Completed (Fiscal Year 1999)
• Budget Amount: ¥185,000,000 (Direct Cost: ¥185,000,000); Fiscal Year 1999: ¥30,000,000 (Direct Cost: ¥30,000,000); Fiscal Year 1998: ¥30,000,000 (Direct Cost: ¥30,000,000); Fiscal Year 1997: ¥30,000,000 (Direct Cost: ¥30,000,000); 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: IFN-γ / シグナル伝達 / Pyk2 / Stat1 / Jakキナーゼ / IL-2受容体 / IRFファミリー転写制御因子 / p53 / NK細胞 / 骨髄微小環境 / ウイルス感染 / IFN-α / β / IRF-1 / IL-15 / 癌抑制遺伝子 / アポトーシス / 癌抑制因子 / CDK抑制因子p21 / lysyl oxidase / IL-2シグナル伝達 / p40^<tax-1> / bcl-2 / IRF-2 / p48 / インターフェロン / IL-2 / 細胞周期 / 転写因子 / チロシンキナーゼ / 遺伝子ノックアウトマウス / 誘導型NO合成酵素

Research Abstract

リンパ球増殖・分化におけるサイトカインシグナルの解析を受容体の下流のシグナル伝達分子の解析を中心に行ってきたが、非受容体型チロシンキナーゼPyk2がIFN-γによってJak2依存性に活性化されることを明らかにした。さらに、Pyk2のドミナントネガティブPKMを用いた実験より、Pyk2はIFN-γによるStat1のセリンリン酸化を担うエフェクター分子であることが解り、Stat1の転写活性化、更に抗ウイルス活性の誘導に深く関与する重要な分子であることを明らかにした。同時に、Jak2により活性化されたPyk2はIFN-γによるErk2の活性化経路にも関与していることも見出ている。また、IL-2シグナル伝達の解析から、IL-2Rγc鎖の膜直下にJak3を介さない新たなシグナル伝達ドメインが存在することを明らかにした。
転写因子IRF-1が細胞レベルでは癌抑制因子として機能し、細胞周期やアポトーシスの制御に重要であることを明らかにしてきたが、マウス個体での解析から、IRF-1欠損単独では自然発癌の発生は上昇しないが、Ha-ras遺伝子のトランスジェニックマウスやp53欠損マウスと掛け合わせることで、これらのマウスが有する潜在的な腫瘍発生の頻度が著明に上昇する事を見出した。特にIRF-1,p53両欠損マウスを作製し解析した結果、このマウスがp53単独欠損に比べ腫瘍の発生率が上昇し、早期に多臓器に腫瘍を発生することが明かとなった。このことから、IRF-1が新規の高発がん感受性遺伝子(tumor susceptibility gene)であることを明らかにした。

Research Products

• [Publications] Takaoka, A.: "Protein tyrosine kinase Pyk2 mediates the Jak-dependent activation of MAPK and Stat1 in IFN-γ, but not IFN-α, signaling"EMBO Journal. 18. 2480-2488 (1999)
• [Publications] Nozawa, H.: "Loss of transcription factor IRF-1 affects tumor susceptibility in mice carrying the Ha-ras transgene or nullizygosity for p53."Genes & Development. 13. 1240-1245 (1999)
• [Publications] Tsujino, S.: "Critical role of the membrane-proximal, proline-rich motif of the interleukin-2 receptor γc chain in the Jak3-independent signal transduction"Genes to Cells. 4. 363-373 (1999)
• [Publications] Matsumoto, M.: "Activation of the transcription factor ISGF3 by interferon-γ"Biological Chemistry. 380. 669-703 (1999)
• [Publications] Ogasawara,K.: "Requirement for IRF-1 in the microenvironment supporting development of natural killer cells." Nature. 391. 700-703 (1998)
• [Publications] Miyazaki,T.: "Pyk2 is a downstream mediator of the IL-2 receptor-coupled Jak signaling pathway." Genes & Development. 12. 770-775 (1998)
• [Publications] Fujii,H.: "Functional dissection of the cytoplasmic subregions of the IL-2 receptor βc chain in primary lymphocyte populations." EMBO Journal. 17. 6551-6557 (1998)
• [Publications] Tanaka,N.: "Type I interferons are essential mediators of apoptotic death in virally infected cells." Genes to Cells. 3. 29-37 (1998)
• [Publications] Sato,M.: "Involvement of the IRF family transcription factor IRF-3 in virus-induced activation of the IFN-β gene." FEBS Letters. 425. 112-116 (1998)
• [Publications] Sato,M.: "Positive feedback regulation of type I IFN genes by the IFN-inducible transcription factor IRF-7." FEBS Letters. 441. 106-110 (1998)
• [Publications] Liu,Z.J.: "A critical role for cyclin C in promotion of the hematopoietic cell cycle by cooperation with c-Myc." Molecullar and Cellular Biology. 18. 3445-3454 (1998)
• [Publications] Nozawa,H.: "Functionally inactivating point mutation in the tumor-suppressor IRF-1 gene identified in human gastric cancer." International Journal of Cancer. 77. 522-527 (1998)
• [Publications] Endo,T.A.et al.: "A new protein containing an SH2 domain that inhibits JAK kinases." Nature. 387. 921-924 (1997)
• [Publications] Kondo,T.et al.: "Identification and characterization of nucleophosmin/B23/numatrin which binds the anti-oncogenic transcription factor IRF-1 and manifests oncogenic activity." Oncogene. 15. 1275-1281 (1997)
• [Publications] Taki,S.et al.: "Multistage regulation of Th1-type immune responses by the transcription factor IRF-1." Immunity. 6. 673-679 (1997)
• [Publications] Taniguchi,T.et al.: "IRF-1 : the transcription factor linking the interferon response and oncogenesis." Biochim.Biophys.Acta.Reviews on Cancer. 1333. M9-17 (1997)
• [Publications] Ogasawara,K.et al.: "Requirement of IRF-1 for the microenvironment supporting natural killer cell development." Nature. 391. 700-703 (1998)
• [Publications] Tanaka,N.et al.: "Type I interferons are essential mediators of apoptotic death in virally-infected cells." Genes to Cells. (発表予定). (1998)
• [Publications] Adachi,M.他: "Interleukin-2 (IL-2) upregulates BAG-1 gene expression through serine-rich region within IL-2 receptor βc chain." Blood. 88. 4118-4123 (1996)
• [Publications] Miyazaki,T.他: "Selective cooperation of HTLV-1-encoded p40^<tax-1> with cellular oncoproteins in the induction of hematopoietic cell proliferation." Oncogene. 12. 2403-2408 (1996)
• [Publications] Miyazaki,T.他: "Coupling of the IL2 receptor complex with non-receptor protein tvrosine kinases." Cancer Surveys. 27. 25-40 (1996)
• [Publications] Tan,R.S-P.他: "Identification of the lysyl oxidase gene as a target of the antioncogenic transcription factor,IRL-1,and its possible role in tumor suppression." Cancer Res.56. 2417-2421 (1996)
• [Publications] Tanaka,N.他: "Cooperation of the tumor suppressors IRF-1 and p53 in response to DNA damage." Nature. 382. 816-818 (1996)
• [Publications] Minami Y: "Protein tyrosine kinase Syk is associated with and activated by the IL-2 receptor,possible link with the c-myc induction pathway" Immunigy. 2. 89-100 (1995)
• [Publications] Kawakami T: "Possible involment of the transcription factor ISGF3γ in virusinduced expression of the IFN-βgene." FEBS Letters. 358. 225-229 (1995)
• [Publications] Uegaki K: "Secondary structure and folding topology of the DNA binding domain of interferon regulatory factor 2,as revealed by NMR soectrisco" FEBS Letter. 359. 184-188 (1995)
• [Publications] Miyazaki T: "Three distinct IL-2 signaling pathways mediated by bcl-2,c-myc and lck cooperate in hematopoietic cell proliferation." Cell. 81. 223-231 (1995)
• [Publications] Taniguchi T: "Cytokine signaling through nonreceptor protein tyrosine kinases." Science. 268. 251-255 (1995)
• [Publications] Fuji H: "Activation of Stat5 by interleukin 2 requires a carboxyl-terminal region of the interleukin 2 receptor β chain but is not essential for the proliferative signal transmission." Proc.Natl.Acad.Sci.USA. 92. 5482-5486 (1995)
• [Publications] Suzuki H: "Dergulated T Cell Activation and Autommunity in Mice Lacking Interleukin-2 Receptor β." Science. 268. 1472-1476 (1995)
• [Publications] Tamura T: "An IRF-1-dependent pathway of DNA damage-induced apoptosis in mitogen-activated T lymphosytes." Nature. 376. 596-599 (1995)
• [Publications] Nobuyuki Tanaka: "Celluar commitment to oncogene-induced transformation or apoptosis is dependent on the transcription factor" Cell. 77. 829-839 (1994)
• [Publications] Torr Kimura: "Involvement of the IRF-1 transcription factor in antiviral responses to interferons" Science. 264. 1921-1924 (1994)
• [Publications] Hisashi Harada: "Accelerated exon skipping of IRF-1 mRNA in human myelodysplasia;leukemia;a possible mechanism" Oncogene. 9. 3313-3320 (1994)
• [Publications] Tadaaki Miyazaki: "Functional activation of Jak1 and Jak3 by selective association with IL-2 receptor subnits" Science. 266. 1045-1047 (1994)
• [Publications] Yasuhiro Minami: "Protein tyrosine kinase Syk is associated with and activated by the IL-2 receptor,possible link with the c-mycinductic pathuay" Immunity. 2. 89-100 (1994)
• [Publications] Tadaaki Miyazaki: "Three distinct IL-2 signaling pathways mediated by bcl-2 c-myc and lck cooperate in hematopoietic cell proliferation." Cell. (in press).