2001 Fiscal Year Annual Research Report

シグナル伝達分子に対する特異的阻害剤の同定と白血病・癌に対する治療への応用

Research Project

Project/Area Number	13218033
Research Institution	The University of Tokyo
Principal Investigator	北村俊雄東京大学, 医科学研究所, 教授 (20282527)
Co-Investigator(Kenkyū-buntansha)	野阪哲哉東京大学, 医科学研究所, 客員助教授 (30218309)
Keywords	シグナル伝達 / トランスレーショナルリサーチ / 白血病 / 内科 / サイトカイン
Research Abstract	我々は、新しい抗白血病剤の開発を目指して恒常的活性型Flt-3に対する特異的阻害剤のスクリーニングを行ないGTP-14564を同定した。GTP14564はは、恒常的活性型Flt-3を発現する白血病細胞株MOLM13および恒常的活性型Flt-3を強制発現させたBa/F3細胞(BaF/ITD-FLT3)のin vitroでの増殖を特異的かつ効率良く抑制した。これらの細胞の増殖は、GTP14564の1mMという比較的低い濃度において完全に抑制されたが、野生型Flt-3発現Ba/F3細胞(BaF/wt-FLT3)をFlt-3リガンドで刺激した場合の増殖を完全に抑制するためには、30-50mMという高い濃度のGTP14564が必要であった。 GTP14564の選択細胞毒性の分子機構を調べるために、まず野生型FLT3(wt-FLT3)と恒常的活性型FLT3(ITD-FLT3)のキナーゼ活性に対するGTP14564の抑制効果を検討した。予想に反してwt-FLT3およびITD-FLT3のキナゼ活性はGTP14564によって同等に抑制された。そこでさらにwt-FLT3およびITD-FLT3下流のシグナル伝達系に対するGTP14564の効果を詳細に解析し、ITD-FLT3の増殖誘導活性が主にSTAT5の活性化によること、STAT5の活性化がBaF/wt-FLT3にくらべBaF/ITD-FLT3においてより効率良くGTP14564で阻害されることを見い出した。またITD-FLT3が異行性にTyk2を活性化することも判明したが、このTyk2活性化はSTAT5の活性化を介してITD-FLT3の細胞トランスフォーム能誘導に関与している可能性もある。

Research Products

(23 results)

All Other

All Publications (23 results)

[Publications] Kagami, S.: "Role of Stat5a in T Helper Cell Differentiation"Blood. 97. 2358-2365 (2001)
[Publications] Hirose, K.: "MgcRacGAP is involved in cytokinesis through associating with mitotic spindle and midbody"J. Biol. Chem.. 276. 5821-5828 (2001)
[Publications] Kamizono, S.: "The SOCS box of SOCS-1 accelerates ubiquitin-dependent proteolysis of TEL-JAK2"J. Biol. Chem.. 276. 12530-12538 (2001)
[Publications] Kawashima, T.: "STAT5 induces macrophage differentiation of M1 leukemia cells through activation of IL-6 production mediated by NF-κB p65"J. Immunol.. 167. 3652-3660 (2001)
[Publications] Tonozuka, Y.: "Molecular cloning of a human novel type I cytokine receptor related to Delta 1"Cytogenetics and Cell Genetics. 93. 23-25 (2001)
[Publications] Ishido, M.: "Cholesterol requirement for receptor transport from multivesicular late endosomes to the Golgi"J. Cell Science. 114. 1965-1976 (2001)
[Publications] Tulin, E.E.: "A novel secreted form of immune suppressor factor with high homology to vacuolar ATPase identified by forward genetic approach of functional screening based on cell proliferation"J. Biol. Chem.. 276. 27519-27526 (2001)
[Publications] Kimura, M.: "Regulation of Th2 cell differentiation by mel-18, a mammalian polycomb group gene"Immunity. 15. 275-287 (2001)
[Publications] Senga, T.: "JAK/Stat3 dependent activation of RalGDS/Ral pathway in M1 mouse myeloid leukemic cells"J. Biol. Chem.. 276. 32678-32681 (2001)
[Publications] Frasor, J.: "Differential roles for Stat5α and Stat5β in prolactin stimulation of estrogen receptor a and b transcription"Molecular Endcrinol. 15. 2172-2181 (2001)
[Publications] Yamamoto, S.: "Proleferation of parenchymal neural progenitors in response to injury in the adult rat spinal cord"Exp. Neurol.. 172. 115-127 (2001)
[Publications] Tokiro, Y.: "Moleular cloning and characterization of mouse tspan-3, a novel member of the tetraspanin superfamily, expressed on resting dendritic cells"Biochem. Biophys. Res. Commun.. 288. 178-183 (2001)
[Publications] Yamashita, Y.: "Sak serine-threonine kinase acts as an effector of Tec tyrosine kinase"J. Biol. Chem.. 276. 39012-39020 (2001)
[Publications] Ueno, M.: "Identification of an embryonic dorsal aorta specific gene, endomucin, and its inhibitory activity on cell adhesion"Biochem. Biophys. Res. Commun.. 287. 501-506 (2001)
[Publications] Ye, S.K.: "The IL-7 receptor controls the accessbility of the TORγ locus by Stat5 and histone acetylation"Immunity. 15. 813-823 (2001)
[Publications] Yamamoto, S.: "Transcription factor expression and Notch-dependent regulation of neural progenitors in the adult rat spinal cord"J. Neurosci.. 21. 9814-9823 (2001)
[Publications] Thlin, E.E.: "SF20,a novel bone marrow stroma-derived factor that binds to mouse TSA-1 and supports lymphoid cell proliferation"J. Immunol.. 167. 6338-6347 (2001)
[Publications] Arakawa, M.: "Negamycin can restore dystrophin in mdx sskeletal muscle"Acta Myologica. 20. 154-158 (2001)
[Publications] Tulin, E.E.: "Genetic approach and phenotype-based complementation screening for identification of stromal cell-derived proteins involved in cell proliferation"Exp. Cell Res.. 272. 23-31 (2002)
[Publications] Tulin, E.E.: "Inhibition of human endothelial cell proliferation by ShIF, a vacuolar H+-ATPAse-like protein"Oncogene. (in press).
[Publications] Nakamura, T.: "Cytokine receptor common β subunit-mediated STAT5 activation confers NFκB activation through IκB-independent mechanism in a murine Pro B cell line Ba/F3"J. Biol. Chem.. (in press).
[Publications] Kitamura, T.: "Role of MgcRacGAP/CYK4 as a regulator of the small GTPase Rho family in cytokinesis and cell differentiation"Cell Structure and Function. (in press).
[Publications] Perez, O.D.: "Acitivation of the PKB/AKT pathway by ICAM-2"Immunity. 16. 51-65 (2002)

2001 Fiscal Year Annual Research Report

シグナル伝達分子に対する特異的阻害剤の同定と白血病・癌に対する治療への応用

Principal Investigator

北村 俊雄 東京大学, 医科学研究所, 教授 (20282527)

Research Products

[Publications] Kagami, S.: "Role of Stat5a in T Helper Cell Differentiation"Blood. 97. 2358-2365 (2001)

[Publications] Hirose, K.: "MgcRacGAP is involved in cytokinesis through associating with mitotic spindle and midbody"J. Biol. Chem.. 276. 5821-5828 (2001)

[Publications] Kamizono, S.: "The SOCS box of SOCS-1 accelerates ubiquitin-dependent proteolysis of TEL-JAK2"J. Biol. Chem.. 276. 12530-12538 (2001)

[Publications] Kawashima, T.: "STAT5 induces macrophage differentiation of M1 leukemia cells through activation of IL-6 production mediated by NF-κB p65"J. Immunol.. 167. 3652-3660 (2001)

[Publications] Tonozuka, Y.: "Molecular cloning of a human novel type I cytokine receptor related to Delta 1"Cytogenetics and Cell Genetics. 93. 23-25 (2001)

[Publications] Ishido, M.: "Cholesterol requirement for receptor transport from multivesicular late endosomes to the Golgi"J. Cell Science. 114. 1965-1976 (2001)

[Publications] Tulin, E.E.: "A novel secreted form of immune suppressor factor with high homology to vacuolar ATPase identified by forward genetic approach of functional screening based on cell proliferation"J. Biol. Chem.. 276. 27519-27526 (2001)

[Publications] Kimura, M.: "Regulation of Th2 cell differentiation by mel-18, a mammalian polycomb group gene"Immunity. 15. 275-287 (2001)

[Publications] Senga, T.: "JAK/Stat3 dependent activation of RalGDS/Ral pathway in M1 mouse myeloid leukemic cells"J. Biol. Chem.. 276. 32678-32681 (2001)

[Publications] Frasor, J.: "Differential roles for Stat5α and Stat5β in prolactin stimulation of estrogen receptor a and b transcription"Molecular Endcrinol. 15. 2172-2181 (2001)

[Publications] Yamamoto, S.: "Proleferation of parenchymal neural progenitors in response to injury in the adult rat spinal cord"Exp. Neurol.. 172. 115-127 (2001)

[Publications] Tokiro, Y.: "Moleular cloning and characterization of mouse tspan-3, a novel member of the tetraspanin superfamily, expressed on resting dendritic cells"Biochem. Biophys. Res. Commun.. 288. 178-183 (2001)

[Publications] Yamashita, Y.: "Sak serine-threonine kinase acts as an effector of Tec tyrosine kinase"J. Biol. Chem.. 276. 39012-39020 (2001)

[Publications] Ueno, M.: "Identification of an embryonic dorsal aorta specific gene, endomucin, and its inhibitory activity on cell adhesion"Biochem. Biophys. Res. Commun.. 287. 501-506 (2001)

[Publications] Ye, S.K.: "The IL-7 receptor controls the accessbility of the TORγ locus by Stat5 and histone acetylation"Immunity. 15. 813-823 (2001)

[Publications] Yamamoto, S.: "Transcription factor expression and Notch-dependent regulation of neural progenitors in the adult rat spinal cord"J. Neurosci.. 21. 9814-9823 (2001)

[Publications] Thlin, E.E.: "SF20,a novel bone marrow stroma-derived factor that binds to mouse TSA-1 and supports lymphoid cell proliferation"J. Immunol.. 167. 6338-6347 (2001)

[Publications] Arakawa, M.: "Negamycin can restore dystrophin in mdx sskeletal muscle"Acta Myologica. 20. 154-158 (2001)

[Publications] Tulin, E.E.: "Genetic approach and phenotype-based complementation screening for identification of stromal cell-derived proteins involved in cell proliferation"Exp. Cell Res.. 272. 23-31 (2002)

[Publications] Tulin, E.E.: "Inhibition of human endothelial cell proliferation by ShIF, a vacuolar H+-ATPAse-like protein"Oncogene. (in press).

[Publications] Nakamura, T.: "Cytokine receptor common β subunit-mediated STAT5 activation confers NFκB activation through IκB-independent mechanism in a murine Pro B cell line Ba/F3"J. Biol. Chem.. (in press).

[Publications] Kitamura, T.: "Role of MgcRacGAP/CYK4 as a regulator of the small GTPase Rho family in cytokinesis and cell differentiation"Cell Structure and Function. (in press).

[Publications] Perez, O.D.: "Acitivation of the PKB/AKT pathway by ICAM-2"Immunity. 16. 51-65 (2002)

北村俊雄東京大学, 医科学研究所, 教授 (20282527)