2002 Fiscal Year Annual Research Report

細胞増殖抑制分子p27の分解機構の研究

Research Project

Project/Area Number	12213097
Research Institution	Kyushu University
Principal Investigator	中山敬一九州大学, 生体防御医学研究所, 教授 (80291508)
Keywords	p27 / ユビキチン化 / KPC / G0-G1移行期 / 細胞周期
Research Abstract	CDKインヒビターp27は、Skp2を含むユビキチンリガーゼ(SCF^<Skp2>)によってユビキチン化されることが知られていた。ところが、われわれが作製したSkp2ノックアウトマウスの解析から、Skp2が欠損するとp27の分解はS〜G2期にかけて傷害されるが、G0-G1移行期におけるp27の分解は正常に起こることがわかった。このことは、G0-G1期においてSCF^<Skp2>以外のユビキチンリガーゼが存在し、p27の量的制御を行っていることを示したものである。そこでわれわれは、G0-G1移行期で働く新規ユビキチンリガーゼを精製し、そのアミノ酸配列の決定を試み、二つのサブユニットからなる複合体がこの機能を有していることが判明した。これらはKPC(Kip1-ubiquitylation Promoting Complex)1およびKPC2と命名され、KPC1とKPC2は複合体を形成し、p27をユビキチン化することができる。KPC1とKPC2は共に細胞質に共発現しており、KPC1とKPC2を細胞に過剰発現させるとp27のG0-G1移行期における分解が促進され、逆にKPC1の変異体とKPC2を過剰発現させると、その分解が遅延することなどから、KPCが細胞質に輸送されてきたp27をユビキチン化することが示唆された。このことは、p27の分解が核外輸送とそれに引き続くユビキチン依存性分解という機構で行われており、これは速やかに細胞周期ブレーキを不活性化するための戦略であると考えられる。

Research Products
(18 results)

All Other

All Publications (18 results)

[Publications] Minamishima, Y.A. et al.: "Recovery of liver mass without proliferation of hepatocytes after partial hepatectomy in Skp2-deficient mice"Cancer Res.. 62. 995-999 (2002)
[Publications] Yoshida, K. et al.: "Involvement of p27^<KIP1> degradation by Skp2 in the regulation of proliferation in response to wounding of corneal epithelium"Invest. Ophthalmol. Vis. Sci.. 43. 364-370 (2002)
[Publications] Koguchi, K. et al.: "Modulation of astrocyte proliferation by cyclin-dependent kinase inhibitor p27Kip1"Glia. 37. 93-104 (2002)
[Publications] Ikebe, C. et al.: "Isolation and characterization of a novel-F-Box protein Pof10 in fission yeast"Biochem. Biophys. Res. Commun.. 290. 1399-1407 (2002)
[Publications] Yamanaka, A. et al.: "Multiple Skp1-related proteins in Caenorhabditis elegans. Diverse patterns of interaction with Cullins and F-box proteins"Curr. Biol.. 12. 267-275 (2002)
[Publications] Kanematsu, T. et al.: "Role of the PLC-related, catalytically inactive protein p130 in GABA_A receptor function"EMBO J.. 21. 1004-1011 (2002)
[Publications] Miyamoto A. et al.: "Increased proliferation of B cells and auto-immunity in mice lacking protein kinase Cδ"Nature. 416. 865-869 (2002)
[Publications] Masuda T. et al.: "Clinical and biological significance of S-phase kinase-associated protein 2 (Skp2) gene expression in gastric carcinoma : modulation of malignant phenotype by Skp2 overexpression, possibly via p27"Cancer Res.. 62. 3819-3825 (2002)
[Publications] Imai, Y. et al.: "CHIP is associated with Parkin, a gene responsible for familial Parkinson's disease, and enhances its ubiquitin ligase activity"Mol. Cell. 10. 55-67 (2002)
[Publications] Garcia-Fernandez. et al.: "Aplidin induces the mitochondrial apoptotic pathway via oxidative stress-mediated JNK and p38 activation and protein kinase Cδ"Oncogene. 21. 7533-7544 (2002)
[Publications] Nakamichi I. et al.: "Formation of Mallory body-like Inclusions and cell death induced by deregulated expression of keratin 18"Mol. Biol. Cell. 13. 3411-3451 (2002)
[Publications] Shimoda K. et al.: "Tyk2 is required for the induction and nuclear translocation of Daxx which regulates IFN-α-induced suppression of B lymphocyte formation"J. Immunol. I. 169. 4707-4711 (2002)
[Publications] Seto Y.et al.: "Enhanced Th2 cell-mediated allergic inflammation in Tyk2-deficient mice"J. Immunol. 170. 1077-1083 (2002)
[Publications] Kaneko C. et al.: "Characterization of the mouse gene for the U-box-type ubiquitin ligase UFD2a"Biochem. Biophys. Res. Commun.. 300. 297-304 (2002)
[Publications] Tomari SI et al.: "Glomerular differentiation in p27 and p57 double-mutant metanephroi"Anat. Embryol.. 206. 31-36 (2002)
[Publications] Shirane M. et al.: "Inherent calcineurin inhibitor FKBP38 targets Bcl-2 to mitochondria and inhibits apoptosis"Nature Cell Biol.. 5. 28-63 (2002)
[Publications] Shimoda, K. et al.: "Partial impairment of interleukin-12 (IL-12) and IL-18 signaling in Tyk2-deficient mice"Blood. 99. 2094-2099 (2002)
[Publications] Ishida N. et al.: "Phosphorylation of p27^<Kip1> on serine 10 is required for its binding to CRM1 and nuclear export"J. Biol. Chem.. 277. 14355-14358 (2002)

2002 Fiscal Year Annual Research Report

細胞増殖抑制分子p27の分解機構の研究

Principal Investigator

中山 敬一 九州大学, 生体防御医学研究所, 教授 (80291508)

Research Products

[Publications] Minamishima, Y.A. et al.: "Recovery of liver mass without proliferation of hepatocytes after partial hepatectomy in Skp2-deficient mice"Cancer Res.. 62. 995-999 (2002)

[Publications] Yoshida, K. et al.: "Involvement of p27^<KIP1> degradation by Skp2 in the regulation of proliferation in response to wounding of corneal epithelium"Invest. Ophthalmol. Vis. Sci.. 43. 364-370 (2002)

[Publications] Koguchi, K. et al.: "Modulation of astrocyte proliferation by cyclin-dependent kinase inhibitor p27Kip1"Glia. 37. 93-104 (2002)

[Publications] Ikebe, C. et al.: "Isolation and characterization of a novel-F-Box protein Pof10 in fission yeast"Biochem. Biophys. Res. Commun.. 290. 1399-1407 (2002)

[Publications] Yamanaka, A. et al.: "Multiple Skp1-related proteins in Caenorhabditis elegans. Diverse patterns of interaction with Cullins and F-box proteins"Curr. Biol.. 12. 267-275 (2002)

[Publications] Kanematsu, T. et al.: "Role of the PLC-related, catalytically inactive protein p130 in GABA_A receptor function"EMBO J.. 21. 1004-1011 (2002)

[Publications] Miyamoto A. et al.: "Increased proliferation of B cells and auto-immunity in mice lacking protein kinase Cδ"Nature. 416. 865-869 (2002)

[Publications] Masuda T. et al.: "Clinical and biological significance of S-phase kinase-associated protein 2 (Skp2) gene expression in gastric carcinoma : modulation of malignant phenotype by Skp2 overexpression, possibly via p27"Cancer Res.. 62. 3819-3825 (2002)

[Publications] Imai, Y. et al.: "CHIP is associated with Parkin, a gene responsible for familial Parkinson's disease, and enhances its ubiquitin ligase activity"Mol. Cell. 10. 55-67 (2002)

[Publications] Garcia-Fernandez. et al.: "Aplidin induces the mitochondrial apoptotic pathway via oxidative stress-mediated JNK and p38 activation and protein kinase Cδ"Oncogene. 21. 7533-7544 (2002)

[Publications] Nakamichi I. et al.: "Formation of Mallory body-like Inclusions and cell death induced by deregulated expression of keratin 18"Mol. Biol. Cell. 13. 3411-3451 (2002)

[Publications] Shimoda K. et al.: "Tyk2 is required for the induction and nuclear translocation of Daxx which regulates IFN-α-induced suppression of B lymphocyte formation"J. Immunol. I. 169. 4707-4711 (2002)

[Publications] Seto Y.et al.: "Enhanced Th2 cell-mediated allergic inflammation in Tyk2-deficient mice"J. Immunol. 170. 1077-1083 (2002)

[Publications] Kaneko C. et al.: "Characterization of the mouse gene for the U-box-type ubiquitin ligase UFD2a"Biochem. Biophys. Res. Commun.. 300. 297-304 (2002)

[Publications] Tomari SI et al.: "Glomerular differentiation in p27 and p57 double-mutant metanephroi"Anat. Embryol.. 206. 31-36 (2002)

[Publications] Shirane M. et al.: "Inherent calcineurin inhibitor FKBP38 targets Bcl-2 to mitochondria and inhibits apoptosis"Nature Cell Biol.. 5. 28-63 (2002)

[Publications] Shimoda, K. et al.: "Partial impairment of interleukin-12 (IL-12) and IL-18 signaling in Tyk2-deficient mice"Blood. 99. 2094-2099 (2002)

[Publications] Ishida N. et al.: "Phosphorylation of p27^<Kip1> on serine 10 is required for its binding to CRM1 and nuclear export"J. Biol. Chem.. 277. 14355-14358 (2002)

中山敬一九州大学, 生体防御医学研究所, 教授 (80291508)