1995 Fiscal Year Annual Research Report

KITレセプターの突然変異によるマスト細胞腫の発生機構

Research Project

Project/Area Number	07670245
Research Category	Grant-in-Aid for General Scientific Research (C)
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	KITレセプターチロシンキナーゼ / 突然変異 / 活性化 / マスト細胞 / トランスジェニックマウス
Research Abstract	レトロウイルスベクターを用いて正常なc-Kitセレプター・チロシンキナーゼ(KIT)をコードする野生型KIT遺伝子およびAspをValに置換した変異型KIT遺伝子をインターロイキン(IL)-3依存性のマスト細胞株(IC-2)とPro-B細胞株(Ba/F3)に導入した。IC-2とBa/F3のいずれの場合でも野生型KIT遺伝子を導入した細胞はIL-3ばかりでなくKITのリガンドであるstem cell factor(SCF)に対しても濃度依存性に増殖するようになった。一方、変異型KIT遺伝子を導入した細胞はIL-3とSCF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の皮下に移植すると腫瘍を形成した後白血病化した。またFMA3マスト細胞腫株のKITは構成的に二量体を形成するために活性化していることを見い出し、この原因がjuxtamembrane領域の7つのアミノ酸の欠失に求められることを示した。マウスの主要組織適合遺伝子複合体クラスIのプロモーターで制御される変異型KIT遺伝子(Asp→Val)をもつトランスジェニックマウスを作製したところ白血病の発症がみられた。突然変異により構成的に活性化するKITは細胞の腫瘍化に直接的に関与していることをものと思われる。

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 RBL-2H3" Int Arch Allergy Immunol. 106. 377-385 (1995)
[Publications] Kitatama,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 culeured mast cells and fibroblasts by phorbol 12-myristate 13-acetate and stemcell factor" Exp Hematol. 23. 58-65 (1995)
[Publications] Kamada,S: "bcl-2 deficiency 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 molecular 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 hemoltyic anemia 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: "Transforming and differentiation-inducing potentials of constitutively activated c-kit mutant genes in the IC-2 murinc interleukin-3-dependent mast cell line" Am J Pathol. 148. 189-200 (1996)
[Publications] Ali,S: "Expression of multiple C-kit receptor messenger ribonucleic acid transeripts during postnatal development of the rat testis" Biochem Biophys Res Com. 218. 104-112 (1996)
[Publications] Moriyama,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

KITレセプターの突然変異によるマスト細胞腫の発生機構

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 RBL-2H3" Int Arch Allergy Immunol. 106. 377-385 (1995)

[Publications] Kitatama,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 culeured mast cells and fibroblasts by phorbol 12-myristate 13-acetate and stemcell factor" Exp Hematol. 23. 58-65 (1995)

[Publications] Kamada,S: "bcl-2 deficiency 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 molecular 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 hemoltyic anemia 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: "Transforming and differentiation-inducing potentials of constitutively activated c-kit mutant genes in the IC-2 murinc interleukin-3-dependent mast cell line" Am J Pathol. 148. 189-200 (1996)

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

[Publications] Moriyama,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)