c-kitがん原遺伝子の発現と機能

• Project/Area Number: 06281111
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Research Institution: Osaka University
• Principal Investigator: 西宗 義武 大阪大学, 微生物病研究所, 教授 (80029793)
• Co-Investigator(Kenkyū-buntansha): 神野 茂樹 東京大学, 医学部, 助手 (10251224) ; 岩間 厚志 熊本大学, 医学部, 助手 (70244126) ; 三浦 恭定 自治医科大学, 教授 (60048965) ; 羽地 達次 九州歯科大学, 助教授 (50156379) ; 松居 靖久 東北大学, 加齢医学研究所, 助教授 (40241575)
• Project Period (FY): 1994
• Project Status: Completed (Fiscal Year 1994)
• Budget Amount: ¥12,600,000 (Direct Cost: ¥12,600,000); Fiscal Year 1994: ¥12,600,000 (Direct Cost: ¥12,600,000)
• Keywords: c-kit / がん原遺伝子 / 精細胞 / マスト細胞 / SCF / W変異 / Sl変異

Research Abstract

精細胞の増殖と分化は出生直後c-kitとは無関係に始まり,やがてc-kitの発現と共にSCF-c-kitの刺激で行なわれることが明かになった。又、c-kitを生殖細胞で特異的に発現させるcDNAを導入したトランスジェニックマウスを作成したところ、初代培養での始原生殖細胞の増殖が亢進することが明かになった。HPV16E6E7トランスジェニックマウスの精巣腫瘍発生にC-Kitとそのリガンド遺伝子が重要な働きをしている事をそれぞれの変異遺伝子を導入する事により証明した。マスト細胞の増殖分化をc-kit遺伝子の上流で制御していると考えられるmi遺伝子は転写因子をコードしているがこの因子がマスト細胞特異的プロテアーゼ遺伝子の転写に直接関与していることを分子レベルで証明した。さらにc-kit遺伝子の活性化点突然変異を導入された骨髄系前駆細胞は腫瘍化する事を示した。このように精細胞及びマスト細胞等の発生と分化に果たすc-kitの役割がかなり明かになると共にc-kitの恒常的活性化がこれらの腫瘍の発生に重要な役割を担っている事が示唆された。

Research Products

• [Publications] Koshimizu U.et al.: "W^n mutation of c-kit receptor affects its post-translational processing and extracellular expression." Oncogene. 9. 157-162 (1994)
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• [Publications] Watanabe D.et al.: "Molecular cloning of a novel Ca2+-binding protein(Calmegin)specifically expressed during male meiotic germ cell development." J.Biol.Chem.269. 7744-7749 (1994)
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• [Publications] Tei H.et al.: "Characterization of mast cells drived from Ws/Ws mast cell-deficient rats with a small deletion at tyrosine kinase domain of c-kit." Blood. 83. 916-925 (1994)
• [Publications] Tsujimura T.et al.: "Ligand-independent activation of c-kit receptor tyrosine kinase in a murine mastcytoma cell line P-815 generated by a point mutation." Blood. 83. 2619-2626 (1994)
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• [Publications] Ebi,Y.et al.: "Effect of mi(microphtalmia)locus on expression of c-kit and proteases in cultured mast cells of mi/mi genotype:low c-kit expression as a causal role of mast cell defect in mi/mi mice." Mol.Biol.Hematopoiesis,. 3. 107-115 (1994)
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• [Publications] Matsubara,N.et al.: "Murine polo like kinase 1 gene is expressed in meiotic testicular germ cells and oocytes." Mol.Reprod.Dev.(in press).
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• [Publications] Jinno S.et al.: "Cdc25A is a novel Phosphatase functioning early in the cell cycle." EMBO J.13. 1549-1556 (1994)
• [Publications] Hanazono,Y.et al.: "Tyrosine-phosphorylation of the proto oncogene product Vav and its association with the adapter Grb2/Ash in a human leukemia cell line UT-7." Jpn.J.,Cancer Res.(in press).
• [Publications] Kitamura,Y.et al.: "Biological and Molecular Aspect of Mast Cell and Basophil Differentiation and Function" Development of mast cells and basophils:role of c-kit receptor tyrosine kinase for differentiation,survival and neoplastic transformation of mast cells.(in press),