2003 Fiscal Year Annual Research Report

活性化変異c-Kit,Flt3の異常シグナル伝達を標的とした治療法の開発

Research Project

Project/Area Number	15025241
Research Institution	Osaka University
Principal Investigator	水木満佐央大阪大学, 医学系研究科, 講師 (80283761)
Co-Investigator(Kenkyū-buntansha)	柴山浩彦大阪大学, 医学系研究科, 助手 (60346202) 松村到大阪大学, 医学系研究科, 助教授 (00294083) 金倉譲大阪大学, 医学系研究科, 教授 (20177489)
Keywords	レセプターチロシンキナーゼ / キナーゼ領域変異 / activation loop / 分子標的療法 / チロシンキナーゼ阻害剤
Research Abstract	チロシンキナーゼのキナーゼ領域内にあるactivation loopの変異によりチロシンキナーゼ阻害剤抵抗性が誘導されることが知られており、これらの変異型チロシンキナーゼの新たな阻害療法の開発が必要とされている。c-Kit、Flt3のactivation loop変異型(c-Kit^<Asp814Val>、Flt3^<Asp838Val>)においてその活性化、シグナル伝達に必須のチロシン残基について検討を行った。c-Kit^<Asp814Val>ではTyr719のPhe置換によってPI3-kinaseのp85subunitの結合が完全に消失し、PI3-kinaseの活性化が失われるだけでなく、キナーゼの活性化自身も著明に抑制され増殖阻害が生じた。またTyr546,Tyr567,Tyr577,Tyr821のPhe置換はc-Kit^<Asp814Val>の増殖抑制を示し、C末端の欠失はc-Kit^<Asp814Val>のキナーゼ活性、増殖ともに抑制した。一方Flt3<Asp838Val>においてはTyr845,Tyr892,Tyr922をPheに変換することでキナーゼ活性の抑制、MAP kinase・STAT3/5シグナルの抑制、増殖・生存の抑制が認められた。Flt3のTyr845とc-KitのTyr821はactivation loop内の保存されたチロシン残基であり、両者が共通してactivation loop領域変異型の活性化およびシグナル伝達に関与していることが明らかとなったが、その他のシグナルに関与するチロシン残基は両変異体で異なっており、C-Kit、Flt3のactivation loop領域変異は、それぞれ特異的活性化機構を有することが明らかとなった。またそれぞれの変異型の活性化に必須のチロシン残基を標的としたチロシンキナーゼ阻害療法の可能性が示された。

Research Products
(12 results)

All Other

All Publications (12 results)

[Publications] Matsumura I: "Molecular mechanisms of E2F1-and c-Myc-enhanced apoptosis."Recent Res.Devel.Mol.Cell Biol.. 4. 311-324 (2003)
[Publications] Mizuki M: "Constitutive active receptor tyrosine kinase in hematological neoplasia"Recent Res.Devel.Mol.Cell Biol.. 4. 85-100 (2003)
[Publications] Hashimoto K: "Necessity of tyrosine 719 and phosphatidylinositol 3'-kinase-mediated signal pathway in constitutive activation and oncogenic potential of c-kit receptor tyrosine kinase with the Asp814Val mutation"Blood. 101・3. 1094-1102 (2003)
[Publications] Mizuki M: "Suppression of myeloid transcription factors and induction of STAT response genes by AML-speciflc Flt3 mutations"Blood. 101・8. 3164-3173 (2003)
[Publications] Zhang X: "Constitutively activated Rho guanosine triphosphatases regulate the growth and morphology of hairy cell leukemia cells"Int.J.Hematol.. 77・3. 263-273 (2003)
[Publications] Kawasaki A: "Opposing effects of PML and PML/RARalpha on STAT3 activity"Blood. 101・9. 3668-3673 (2003)
[Publications] Matsumura I: "E2F1 and c-Myc in cell growth and death"Cell Cycle.. 2・4. 333-338 (2003)
[Publications] Mizuki M: "Oncogenic receptor tyrosine kinase in leukemia"Cell Mol Biol.. 49・6. 907-922 (2003)
[Publications] Kataoka Y: "Reciprocal inhibition between MyoD and STAT3 in the regulation of growth and differentiation of myoblasts"J Biol Chem.. 278・45. 44178-44187 (2003)
[Publications] Saeki Y: "Enhanced production of osteopontin in multiple myeloma : clinical and pathogenic implications"Br J Haematol. 123・2. 263-270 (2003)
[Publications] Takakuwa T: "Establishment and characterization of unique cell lines derived from pyothorax-associated lymphoma which develops in long-standing pyothorax and is strongly associated with Epstein-Barr virus infection"Cancer Sci.. 94・10. 858-863 (2003)
[Publications] Matsumura I: "Cell cycle regulation in hematopoietic stem cells"Res Adv in Blood. 2. 39-49 (2003)

2003 Fiscal Year Annual Research Report

活性化変異c-Kit,Flt3の異常シグナル伝達を標的とした治療法の開発

Principal Investigator

水木 満佐央 大阪大学, 医学系研究科, 講師 (80283761)

Research Products

[Publications] Matsumura I: "Molecular mechanisms of E2F1-and c-Myc-enhanced apoptosis."Recent Res.Devel.Mol.Cell Biol.. 4. 311-324 (2003)

[Publications] Mizuki M: "Constitutive active receptor tyrosine kinase in hematological neoplasia"Recent Res.Devel.Mol.Cell Biol.. 4. 85-100 (2003)

[Publications] Hashimoto K: "Necessity of tyrosine 719 and phosphatidylinositol 3'-kinase-mediated signal pathway in constitutive activation and oncogenic potential of c-kit receptor tyrosine kinase with the Asp814Val mutation"Blood. 101・3. 1094-1102 (2003)

[Publications] Mizuki M: "Suppression of myeloid transcription factors and induction of STAT response genes by AML-speciflc Flt3 mutations"Blood. 101・8. 3164-3173 (2003)

[Publications] Zhang X: "Constitutively activated Rho guanosine triphosphatases regulate the growth and morphology of hairy cell leukemia cells"Int.J.Hematol.. 77・3. 263-273 (2003)

[Publications] Kawasaki A: "Opposing effects of PML and PML/RARalpha on STAT3 activity"Blood. 101・9. 3668-3673 (2003)

[Publications] Matsumura I: "E2F1 and c-Myc in cell growth and death"Cell Cycle.. 2・4. 333-338 (2003)

[Publications] Mizuki M: "Oncogenic receptor tyrosine kinase in leukemia"Cell Mol Biol.. 49・6. 907-922 (2003)

[Publications] Kataoka Y: "Reciprocal inhibition between MyoD and STAT3 in the regulation of growth and differentiation of myoblasts"J Biol Chem.. 278・45. 44178-44187 (2003)

[Publications] Saeki Y: "Enhanced production of osteopontin in multiple myeloma : clinical and pathogenic implications"Br J Haematol. 123・2. 263-270 (2003)

[Publications] Takakuwa T: "Establishment and characterization of unique cell lines derived from pyothorax-associated lymphoma which develops in long-standing pyothorax and is strongly associated with Epstein-Barr virus infection"Cancer Sci.. 94・10. 858-863 (2003)

[Publications] Matsumura I: "Cell cycle regulation in hematopoietic stem cells"Res Adv in Blood. 2. 39-49 (2003)

水木満佐央大阪大学, 医学系研究科, 講師 (80283761)