1995 Fiscal Year Annual Research Report

活性化KIT遺伝子の導入によるマスト細胞腫高発マウスの作製

Research Project

Project/Area Number	07272225
Research Institution	Osaka University
Principal Investigator	辻村亨大阪大学, 医学部, 助手 (20227408)
Co-Investigator(Kenkyū-buntansha)	北村幸彦大阪大学, 医学部, 教授 (70028520) 岡部勝大阪大学, 微生物研究所・感染動物実験施設, 助教授 (30089875)
Keywords	C-kit遺伝子 / 突然変異 / 発がん / マスト細胞 / トランスジエニックマウス
Research Abstract	c-kitレセプター・チロシンキナーゼ(KIT)のAspをValに置換した活性型KIT遺伝子をインターロイキン(IL)-3依存性の培養マスト細胞株(IC-2)に導入すると、導入細胞はIL-3とKITのリガンドであるstem cell factorの両方を含まない培地でも活発に増殖するようになりヌードマウスにおいて造腫瘍性を示した。自律性に増殖する培養マスト細胞腫株(FMA3)ではKITが構成的に二量体を形成するために活性化していた。この原因はjux tamembrane領域の7つのアミノ酸が欠失することに求められた。この新しいタイプの“gain-of-function"突然変異をもつ変異型KIT遺伝子をIC-2細胞に導入すると、導入細胞は自律性に増殖するようになりヌードマウスにおいて腫瘍を形成した。この結果は突然変異によるKITの構成的な活性化がマスト細胞の腫瘍化に深く関与していることを示した。そこでマスト細胞で強く発現するプロテアーゼの1つであるmouse mast cell protease-6(MMCP-6)遺伝子のプロモーターで制御されるヒトの活性型KIT遺伝子(Asp→Val)を導入したトランジェニックマウスを作製した。このトランスジェニックスマウスは突然変異によるKITの構成的な活性化がマスト細胞の腫瘍化に直接的に関与していることを示す良いモデルになると考えられる。

Research Products

(12 results)

All Other

All Publications (12 results)

[Publications] Tsujimura,T: "Substitution of an aspartic acid results in constitutive activation of c-kit receptor tyrosine kinase in a rat tumor mast cell line PBL-2H3" Int Arch Allergy Immunol. 106. 377-385 (1995)
[Publications] Kitayama,H: "Constitutive activating mutations of c-kit receptor tyrosine kinase confer factorindependent growth and tumorigenicity of factor-dependent hematopoietic cell lines" Blood. 85. 790-798 (1995)
[Publications] Adachi,S: "Inhibition of attachment between cultured mast cells and fibroblasts by phorbol 12-myristate 13-acetate and stemcell factor" Exp Hematol. 23. 58-65 (1995)
[Publications] Kamada,S: "bcl-2 deficienecy in mice leads to pleitropic anbormalities: Accelerated lymphoid cell death in thymus and spleen,polycystic kidney, hair hypopigmentation, and distorted small intestine" Cancer Res. 55. 354-359 (1995)
[Publications] Matsumura,I: "Growth response of acute myeloblastic leukemia cells to recombinant human thrombopoietin" Blood. 86. 703-709 (1995)
[Publications] Kitamura,Y: "Regulation of development, survival and neoplastic growth of mast cells through c-kit receptor" Int Arch Allergy Immunol. 107. 54-56 (1995)
[Publications] Kanno,H: "Primary structure of murine red cell-type pyruvate kinase(PK)and molccular characterization of PK deficiency identified in the CBA strain" Blood. 86. 3205-3210 (1995)
[Publications] Morimoto,M: "Pyruvate kinase deficiency of mice associated with nonspherocytic hemolytic ancmia and cure of the ancmia by marrow transplantation without host irradiation" Blood. 86. 4323-4330 (1995)
[Publications] Tsujimura,T: "Constitutive activation of c-kit in FMA3 murine mastocytoma cells caused by deletion of seven amino acids at the juxtamembrane domain" Blood. 87. 273-283 (1996)
[Publications] Hashimoto,K: "Transforming and differentiation-inducing potentials of constitutively activated c-kit mutant genes in the lC-2 murine interlcukin-3-dependent mast cell line" Am J Pathol. 148. 189-200 (1996)
[Publications] Ali,S: "Expression of multiple C-kit receptor messenger ribonuclec acid transcripts during postnatal development of the rat testis" Biochem Biophys Res Com. 218. 104-112 (1996)
[Publications] Moryama,Y: "Role of aspartic acid 814 in the function and expression of c-kit receptor tyrosine kinase" J Biol chem. (in press).

1995 Fiscal Year Annual Research Report

活性化KIT遺伝子の導入によるマスト細胞腫高発マウスの作製

Principal Investigator

辻村 亨 大阪大学, 医学部, 助手 (20227408)

Research Products

[Publications] Tsujimura,T: "Substitution of an aspartic acid results in constitutive activation of c-kit receptor tyrosine kinase in a rat tumor mast cell line PBL-2H3" Int Arch Allergy Immunol. 106. 377-385 (1995)

[Publications] Kitayama,H: "Constitutive activating mutations of c-kit receptor tyrosine kinase confer factorindependent growth and tumorigenicity of factor-dependent hematopoietic cell lines" Blood. 85. 790-798 (1995)

[Publications] Adachi,S: "Inhibition of attachment between cultured mast cells and fibroblasts by phorbol 12-myristate 13-acetate and stemcell factor" Exp Hematol. 23. 58-65 (1995)

[Publications] Kamada,S: "bcl-2 deficienecy in mice leads to pleitropic anbormalities: Accelerated lymphoid cell death in thymus and spleen,polycystic kidney, hair hypopigmentation, and distorted small intestine" Cancer Res. 55. 354-359 (1995)

[Publications] Matsumura,I: "Growth response of acute myeloblastic leukemia cells to recombinant human thrombopoietin" Blood. 86. 703-709 (1995)

[Publications] Kitamura,Y: "Regulation of development, survival and neoplastic growth of mast cells through c-kit receptor" Int Arch Allergy Immunol. 107. 54-56 (1995)

[Publications] Kanno,H: "Primary structure of murine red cell-type pyruvate kinase(PK)and molccular characterization of PK deficiency identified in the CBA strain" Blood. 86. 3205-3210 (1995)

[Publications] Morimoto,M: "Pyruvate kinase deficiency of mice associated with nonspherocytic hemolytic ancmia and cure of the ancmia by marrow transplantation without host irradiation" Blood. 86. 4323-4330 (1995)

[Publications] Tsujimura,T: "Constitutive activation of c-kit in FMA3 murine mastocytoma cells caused by deletion of seven amino acids at the juxtamembrane domain" Blood. 87. 273-283 (1996)

[Publications] Hashimoto,K: "Transforming and differentiation-inducing potentials of constitutively activated c-kit mutant genes in the lC-2 murine interlcukin-3-dependent mast cell line" Am J Pathol. 148. 189-200 (1996)

[Publications] Ali,S: "Expression of multiple C-kit receptor messenger ribonuclec acid transcripts during postnatal development of the rat testis" Biochem Biophys Res Com. 218. 104-112 (1996)

[Publications] Moryama,Y: "Role of aspartic acid 814 in the function and expression of c-kit receptor tyrosine kinase" J Biol chem. (in press).

辻村亨大阪大学, 医学部, 助手 (20227408)