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2002 Fiscal Year Final Research Report Summary

Mechanisms of growth, survival and transformation mediated by KIT and FLT3

Research Project

Project/Area Number 13671063
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionOsaka University

Principal Investigator

KURATSUNE Hirohiko  Osaka University, Graduate School Of Medicine, Associate Professor, 医学系研究科, 助教授 (50195533)

Co-Investigator(Kenkyū-buntansha) MIZUKI Masao  Osaka University, Graduate School Of Medicine, Assistant Professor, 医学系研究科, 助手 (80283761)
MATSUMURA Itaru  Osaka University, Graduate School Of Medicine, Lecturer, 医学系研究科, 講師 (00294083)
KANAKURA Yuzuru  Osaka University, Graduate School Of Medicine, Professor, 医学系研究科, 教授 (20177489)
SHIBAYAMA Hirohiko  Osaka University, Graduate School Of Medicine, Assistant Professor, 医学系研究科, 助手 (60346202)
Project Period (FY) 2001 – 2002
KeywordsReceptor tyrosine kinase / mutation / Acute myeloid leukemia / chemotaixs / Targeting therapy / STAT / inhibitor
Research Abstract

l. Cytoplasmic tyrosine residues involved in KIT-signal transduction
We analyzed effects of phenylalanine conversion of 22 tyrosine residues in the cytoplasmic domain on KIT-mediated cell function. In the wild type KIT, although the proliferation and survival was not affected by these Tyr->Phe conversions, the conversions of Tyr 567, 569, or 719 suppressed the cell migration mediated by KIT/SCF interaction. Tyr567 activated Src family kinase, p38 MAPkinase, which induced Ca2+ influx and the subsequent activation of Erk. Tyr 719 activated PI3-kinase, which induced Ca2+ influx. Both pathways synergistically induced the cell migration. In the constitutively active KIT mutant of kinase domain, Phe conversion of Tyr 719 abolished the kinase activity and the proliferative activity, which suggested that Tyr 719 and associated PI3-kinase is critical for kinase and transforming activity.
2. Targeting inhibition of constitutive active KITTyrosine kinase inhibitors, STI571 and AG1296 suppressed the kinase activity of juxtamembrane domain KIT mutant more effectively than wild type. In contrast, kinase domain mutant resisted to these inhibitors, even though in combination. Therefore, the sensitivity to the inhibitor differs dependent on the type of mutant.
3. FIt3 mutation specific target genes Microchip analysis revealed that Flt3 internal tandem duplication (Flt3-ITD) mutation specifically induced STAT3/5 target genes such as pim-2, SOCS3 and CIS. Flt3-ITD specifically suppressed myeloid-specific transcription factors such as C/EBPalpha and Pu. 1, which suggested that Flt3-ITD is involved in the differentiation block in AML.

  • Research Products

    (15 results)

All Other

All Publications (15 results)

  • [Publications] Shuji Ueda: "Critical roles of c-Kit tyrosine residues 567 and 719 in stem cell factor-induced chemotaxis : contribution of src family kinase and PI3-kinase on calcium mobilization and cell migration"Blood. 99. 3342-3349 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Hirokazu Tanaka: "E2F-1 and c-Myc potentiate apoptosis through inhibition NF-κB that facilitates MnSOD-mediated ROS elimination"Molecular Cell. 9. 1017-1029 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Junko Sonoyama: "Functional Cooperation among Ras, STAT5, and PI3-K Is Required for Full Oncogenic Activities of BCR/ABL in K562 Cells"J. Biol. Chem. 277. 8076-8082 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Shuji Ueda: "Constitutive activation of c-kit by the juxtamembrane but not the catalytic domain mutations is inhibited selectively by tyrosine kinase inhibitors STI571 and AG1296"Int. J. Hematol. 76. 427-435 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Koji Hashimoto: "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 D814V mutation"Blood. 101. 1094-1102 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Masao Mizuki: "Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations"Blood. 101. 3164-3173 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kawasaki, A.: "Down-regulation of an AIM-1 kinase couples with megakaryocytic polyploidization of human hematopoietic cells."J. Cell Biol.. 152. 275-288 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ueda, S.: "Critical roles of c-kit tyrosine residues 567 and 719 in stem cell factor-induced chemotaxis: contribution of src family kinase and PI3-kinase on calcium mobilization and cell migrarion."Blood. 99. 3342-3349 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tanaka,H.: "E2F-1 and c-Myc potentiate apoptosis through inhibition NF-kB that facilitates MnSOD- mediated ROS elimination."Molecular Cell. 9. 1017-1029 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ezoe, S.: "GATA-2/estrogen receptor chimeza regulates cytokine-dependent growth of hematopoiesis through accumulation of p21^<WAF>1 and p27^<KiP1> proteins."Blood. 100. 3512-3520 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Sonoyama, J.: "Functional cooperation among Ras, STAT5 and PI3-K is required for full oncogenic activities of BCR/ABL in K562 cells."J. Biol. Chem.. 277. 8076-8082 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ueda, S.: "Constitutive activation of e-kit by the juxtamembrane but not the catalytic domain mutations is inhibited selectively by tyrosine kinase inhibitors STI571 and AG1296."Int J. Hematol.. 76. 427-435 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Hashimoto, K.: "Necessity of tyrosine 719 and phosphatidylinositol 3'-kinase-mecliated signal pathway in constitutive activation and oncogenic potential of c-kit receptor tyrosine kinase with the D814V mutation."Blood. 101. 1094-1102 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kawasaki, A.: "Opposing Effects of PML, and PML/RARα on STAT3 activiry."Blood. 101(9). 3668-3673

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Mizuki, M.: "Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations."Blood. 101(8). 3164-3173

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2004-04-14  

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