1994 Fiscal Year Annual Research Report

がん細胞におけるアポトーシスの誘因と機構並びにその制御に関する研究

Research Project

Project/Area Number	06281117
Research Institution	National Cancer Center Research Institute and Research Center for Innovative Oncology, National Cancer Center Hospital East
Principal Investigator	口野嘉幸国立がんセンター研究所, 生物物理部, 部長 (60124418)
Co-Investigator(Kenkyū-buntansha)	須田貴司大阪バイオサイエンス研究所, 研究員 (70250090) 林直之九州大学, 医学部, 助手 (50253456) 高橋秀史札幌医科大学, 病理学教室, 助手 (40231394) 仙道富士郎山形大学, 医学部, 教授 (80091833) 内藤幹彦東京大学, 分子細胞生物研究所, 助手 (00198011)
Keywords	アポトーシス / 生体防御 / s-myc遺伝子 / Fas / Fasリガンドシステム / 温度感受性変異株 / アポトーシス耐性変異株 / アポトーシス抑制因子 / シグナル伝達
Research Abstract	アポトーシスは遺伝子レベルで制御された、核破壊を伴う細胞死の一型である。近年、固体の発生や細胞の分化の過程などで見られる細胞の死が主にこの形態をとること、さらには細胞の放射線や化学療法剤、キラーT細胞などの宿主免疫細胞の攻撃等に基づく死もこの機構によること、その発生や調節に種々のがん遺伝子やがん抑制遺伝子が関与していることなどが明らかになってきた。アポトーシスはまた、遺伝子変異などを起こした細胞などの増殖を阻止し、それらを殺傷排除することでがんの発生を未然に防ぐ、生体防御の役割を果たしている重要な機構であることもわかってきた。このようにアポトーシスは、がんの発生や進展の仕組みを知るだけではなく、がんの進展阻止やがん細胞の殺傷除去に関する方策を考えていく上での重要な知見を提供してくれる研究としても注目されるようになり、各方面で活発な研究が行われるようになってきた。そこで本研究班ではとくに、がん細胞におけるアポトーシス発生のメカニズムを多面的に、かつ分子レベルで理解することに努め、そこからえられる情報をもとに、がん細胞に細胞死を誘導できる遺伝子や薬剤等の探索を行い、それらのがん治療への応用を積極的に進めていくことを目的とし、研究を行っている。今年度においては(1)s-myc遺伝子がヒトやラットのグリオーマ細胞に対する有効なアポトーシス誘導因子であると同時に、免疫療法剤としてグリオーマの治療に応用できる可能性が示された(2)Fasリガンドの構造が解析されさらにFas耐性変異細胞株が樹立されたことで、免疫細胞の成熟や細胞傷害性リンパ球による標的細胞の傷害反応等において重要な働きをしているFas/Fasリガンドシステムによるアポトーシス誘導機構が分子レベルで理解できるようになった。(3)アポトーシス耐性変異細胞株や温度感受性変異細胞株が樹立され、Bcl-2とは異なったタイプのアポトーシス抑制因子の存在が明らかになった(4)自然免疫に関与する好中球では、その活性化によって産生されるNOが、標的細胞の傷害反応でみられる細胞死誘導の原因物質であることがわかった、などの点が明らかにされ、アポトーシスに関わるシグナル伝達の機構解明に大きく貢献した。またs-myc遺伝子のように、アポトーシス誘導因子が、がんの治療に応用可能であることが示されたことも本研究の大きな成果である。

Research Products
(20 results)

All Other

All Publications (20 results)

[Publications] Asai,A.,Kuchino,Y.,et al.: "The s-Myc protein having the ability to induce apoptosis is selectively expressed in rat embryo chondrocytes." Oncogene. 9. 2345-2352 (1994)
[Publications] Asai,A.,Kuchino,Y.,et al.: "Negative effects of wild-type p53 and s-Myc on celluar growth and tumorigenicity of glioma cells:Implication of the tumor suppressor genes for gene therapy." Journal of Neuro-Oncology. 19. 259-268 (1994)
[Publications] Asai,A.,Kuchino,Y.,et al.: "Modulation of tumor immunogenicity of rat glioma cells by s-Myc expression:Eradication of rat glioma in vivo." Cell Growth & Differentiation. 5. 1153-1158 (1994)
[Publications] Yamada,M.and Hatanaka,H.: "Interleukin-6 protects cultured rat hippocampal neurons against glutamate-induced cell death." Brain Research. 643. 173-180 (1994)
[Publications] Akaneya,Y.and Hatanaka,H.: "Death of cultured postnatal rat CNS neurons by in vitro hypoxia with special reference to N-methyl-D-aspartate-related toxicity." Neuroscience Research. 19. 279-285 (1994)
[Publications] Nakamura,M.Hatanaka,H.,et al.: "High potassium and cyclic AMP analog promote neuronal survival of basal forebrain cholinergic neurons in culture ftrom postnatal two-week-old rats." Development Brain Research. 81. 218-229 (1994)
[Publications] Takahashi,T.,Suda,T.,et al.: "Human Fas ligand;gene structure,chromosomal location and species specificity." International Immunology. 6. 1567-1574 (1994)
[Publications] Takahashi,T.Suda,T.,et al.: "Generalized lymphoproliferative disease in mice,caused by a point mutation in the Fas ligand." Cell. 76. 969-976 (1994)
[Publications] Suda,T.and Nagata,S.: "Purification and characterization of the Fas-ligand that induces apoptosis." Journal of Experimental Medicine. 179. 873-878 (1994)
[Publications] Klemi,P.J.,Takahashi,S.,et al.: "Immunohistochemical detection of p53 ptotein in borderline and malignant serous ovarian tumors." International Journal Gynecological Pathology. 13. 228-233 (1994)
[Publications] Kataoka,S.,Naito,M.,et al.: "Resistance to antitumor agent-inguced apoptosis in a mutant of human myeloid leukemia U937 cells." Experimental Cell Research. 215. 199-205 (1994)
[Publications] Lee,J.-H.,Naito,M.,et al.: "Nonenzymatic reductive activation of 7-N{{2-{[2-(r-L-glutamyl-amino)etyl]-dithio}ethyl}}mitomycin C by thiol molecules:a novel mitomycin C derivative effecive on mitomycin C-resistant tumor cells." Cancer Research. 54. 2398-2403 (1994)
[Publications] Tsubata,T.,et al.: "Antigen receptor cross-linking induces peritoneal B-cell apoptosis in normal but not autoimmunity-prone mice." Current Biology. 4. 8-17 (1994)
[Publications] Nishitani,S.,Tsubata,T.,et al.: "Lineage marker-negative lymphocyte precursors derived from embryonic stem cells in vitro differentiate into mature lymphocytes in vivo." International Immunology. 6. 909-916 (1994)
[Publications] Tsubata,T.,et al.: "Molecular mechanisms for B lymphocyte selection:induction and regulation of antigen receptor-mediated apoptosis of mature B cells in normal mice and their defect in autoimmunity-prone mice." Proceedings of the Royal Society of London,Series B:Biological Sciences. 345. 297-301 (1994)
[Publications] Noguchi,E.,Hayashi,N.,et al.: "Minimum essential region of CCG1/TAFII250 required for complementing the temperature-sensitive cell cycle mutants,tsBN462 and ts13 cells,of hamster BHK21 cells." Somatic Cell and Molecular Genetics. 20. 505-513 (1994)
[Publications] Tanuma,S.,et al.: "Multiple forms of nuclear deoxyribonuclease in rat thymocytes." Biochemical and Biophysical Research Communications. 203. 789-797 (1994)
[Publications] Shiokawa,D.,Tanuma,S.et al: "Identification of an endonuclease responsible for apoptosis in rat thymocytes." European Journal of Biochemistry. 226. 23-30 (1994)
[Publications] Natsuka,S.,Zenita,K.,et al.: "Molecular cloning of a cDNA encoding a novel human leukocyte α-1,3-fucosyl-transferase capable of synthesizing the sialy Lewis x determinant." Journal of Biological Chemistry. 269. 16789-16794 (1994)
[Publications] Tanaka,T.,Tanaka,K.,et al.: "An acute myeloid leukemia gene,AML1,regukates hemopoietic myeloid cell differentiation and transcriptional activation antagonistically by two alternativespliced forms." EMBO Journal. 14. 341-350 (1994)

1994 Fiscal Year Annual Research Report

がん細胞におけるアポトーシスの誘因と機構並びにその制御に関する研究

Principal Investigator

口野 嘉幸 国立がんセンター研究所, 生物物理部, 部長 (60124418)

Research Products

[Publications] Asai,A.,Kuchino,Y.,et al.: "The s-Myc protein having the ability to induce apoptosis is selectively expressed in rat embryo chondrocytes." Oncogene. 9. 2345-2352 (1994)

[Publications] Asai,A.,Kuchino,Y.,et al.: "Negative effects of wild-type p53 and s-Myc on celluar growth and tumorigenicity of glioma cells:Implication of the tumor suppressor genes for gene therapy." Journal of Neuro-Oncology. 19. 259-268 (1994)

[Publications] Asai,A.,Kuchino,Y.,et al.: "Modulation of tumor immunogenicity of rat glioma cells by s-Myc expression:Eradication of rat glioma in vivo." Cell Growth & Differentiation. 5. 1153-1158 (1994)

[Publications] Yamada,M.and Hatanaka,H.: "Interleukin-6 protects cultured rat hippocampal neurons against glutamate-induced cell death." Brain Research. 643. 173-180 (1994)

[Publications] Akaneya,Y.and Hatanaka,H.: "Death of cultured postnatal rat CNS neurons by in vitro hypoxia with special reference to N-methyl-D-aspartate-related toxicity." Neuroscience Research. 19. 279-285 (1994)

[Publications] Nakamura,M.Hatanaka,H.,et al.: "High potassium and cyclic AMP analog promote neuronal survival of basal forebrain cholinergic neurons in culture ftrom postnatal two-week-old rats." Development Brain Research. 81. 218-229 (1994)

[Publications] Takahashi,T.,Suda,T.,et al.: "Human Fas ligand;gene structure,chromosomal location and species specificity." International Immunology. 6. 1567-1574 (1994)

[Publications] Takahashi,T.Suda,T.,et al.: "Generalized lymphoproliferative disease in mice,caused by a point mutation in the Fas ligand." Cell. 76. 969-976 (1994)

[Publications] Suda,T.and Nagata,S.: "Purification and characterization of the Fas-ligand that induces apoptosis." Journal of Experimental Medicine. 179. 873-878 (1994)

[Publications] Klemi,P.J.,Takahashi,S.,et al.: "Immunohistochemical detection of p53 ptotein in borderline and malignant serous ovarian tumors." International Journal Gynecological Pathology. 13. 228-233 (1994)

[Publications] Kataoka,S.,Naito,M.,et al.: "Resistance to antitumor agent-inguced apoptosis in a mutant of human myeloid leukemia U937 cells." Experimental Cell Research. 215. 199-205 (1994)

[Publications] Lee,J.-H.,Naito,M.,et al.: "Nonenzymatic reductive activation of 7-N{{2-{[2-(r-L-glutamyl-amino)etyl]-dithio}ethyl}}mitomycin C by thiol molecules:a novel mitomycin C derivative effecive on mitomycin C-resistant tumor cells." Cancer Research. 54. 2398-2403 (1994)

[Publications] Tsubata,T.,et al.: "Antigen receptor cross-linking induces peritoneal B-cell apoptosis in normal but not autoimmunity-prone mice." Current Biology. 4. 8-17 (1994)

[Publications] Nishitani,S.,Tsubata,T.,et al.: "Lineage marker-negative lymphocyte precursors derived from embryonic stem cells in vitro differentiate into mature lymphocytes in vivo." International Immunology. 6. 909-916 (1994)

[Publications] Noguchi,E.,Hayashi,N.,et al.: "Minimum essential region of CCG1/TAFII250 required for complementing the temperature-sensitive cell cycle mutants,tsBN462 and ts13 cells,of hamster BHK21 cells." Somatic Cell and Molecular Genetics. 20. 505-513 (1994)

[Publications] Tanuma,S.,et al.: "Multiple forms of nuclear deoxyribonuclease in rat thymocytes." Biochemical and Biophysical Research Communications. 203. 789-797 (1994)

[Publications] Shiokawa,D.,Tanuma,S.et al: "Identification of an endonuclease responsible for apoptosis in rat thymocytes." European Journal of Biochemistry. 226. 23-30 (1994)

[Publications] Natsuka,S.,Zenita,K.,et al.: "Molecular cloning of a cDNA encoding a novel human leukocyte α-1,3-fucosyl-transferase capable of synthesizing the sialy Lewis x determinant." Journal of Biological Chemistry. 269. 16789-16794 (1994)

[Publications] Tanaka,T.,Tanaka,K.,et al.: "An acute myeloid leukemia gene,AML1,regukates hemopoietic myeloid cell differentiation and transcriptional activation antagonistically by two alternativespliced forms." EMBO Journal. 14. 341-350 (1994)

口野嘉幸国立がんセンター研究所, 生物物理部, 部長 (60124418)