Degradation of the cyclin-dependent-kinase inhibitor p27Kip1 is instigated by Jab1

The proliferation of mammalian cells is under strict control, and the cyclin-dependent-kinase inhibitory protein p27Kip1 is an essential participant in this regulation both in vitro and in vivo . Although mutations in p27Kip1 are rarely found in human tumours, reduced expression of the protein correlates well with poor survival among patients with breast or colorectal carcinomas, suggesting that disruption of the p27Kip1 regulatory mechanisms contributes to neoplasia. The abundance of p27Kip1 in the cell is determined either at or after translation, for example as a result of phosphorylation by cyclinE/Cdk2 complexes,, degradation by the ubiquitin/proteasome pathway, sequestration by unknown Myc-inducible proteins, binding to cyclinD/Cdk4 complexes, or inactivation by the viral E1A oncoprotein. We have found that a mouse 38K protein (p38) encoded by the Jab1 gene interacts specifically with p27Kip1 and show here that overexpression of p38 in mammalian cells causes the translocation of p27Kip1 from the nucleus to the cytoplasm, decreasing the amount of p27Kip1 in the cell by accelerating its degradation. Ectopic expression of p38 in mouse fibroblasts partially overcomes p27Kip1-mediated arrest in the G1 phase of the cell cycle and markedly reduces their dependence on serum. Our findings indicate that p38 functions as a negative regulator of p27Kip1 by promoting its degradation.

[1]  P Bucher,et al.  The PCI domain: a common theme in three multiprotein complexes. , 1998, Trends in biochemical sciences.

[2]  James M. Roberts,et al.  Requirement of p27Kip1 for Restriction Point Control of the Fibroblast Cell Cycle , 1996, Science.

[3]  R. Scarborough,et al.  Ligand Cross-reactivity within the Protease-activated Receptor Family* , 1996, The Journal of Biological Chemistry.

[4]  L. Hengst,et al.  Translational Control of p27Kip1 Accumulation During the Cell Cycle , 1996, Science.

[5]  E. Nishida,et al.  A Novel Regulatory Mechanism in the Mitogen-activated Protein (MAP) Kinase Cascade , 1997, The Journal of Biological Chemistry.

[6]  D. Fujiwara,et al.  Leptomycin B targets a regulatory cascade of crm1, a fission yeast nuclear protein, involved in control of higher order chromosome structure and gene expression. , 1994, The Journal of biological chemistry.

[7]  F. Hirahara,et al.  Expression of gelatinase A, tissue inhibitor of metalloproteinases-2, matrilysin, and trypsin(ogen) in lung neoplasms: an immunohistochemical study. , 1997, Human pathology.

[8]  V. Wheaton,et al.  Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation , 1991, Cell.

[9]  S. Coughlin,et al.  Protease-activated receptor 3 is a second thrombin receptor in humans , 1997, Nature.

[10]  P. Beer-Romero,et al.  Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. , 1995, Science.

[11]  B. Amati,et al.  Growth arrest by the cyclin‐dependent kinase inhibitor p27Kip1 is abrogated by c‐Myc. , 1996, The EMBO journal.

[12]  H. Okayama,et al.  High-efficiency transformation of mammalian cells by plasmid DNA. , 1987, Molecular and cellular biology.

[13]  T. Toda,et al.  A new group of conserved coactivators that increase the specificity of AP-1 transcription factors , 1996, Nature.

[14]  C. Sherr Cancer Cell Cycles , 1996, Science.

[15]  T. Hunter,et al.  Inactivation of p27Kip1 by the viral E1A oncoprotein in TGFβ-treated cells , 1996, Nature.

[16]  Minami Matsui,et al.  The COP9 complex is conserved between plants and mammals and is related to the 26S proteasome regulatory complex , 1998, Current Biology.

[17]  P. O'Byrne,et al.  Tachyphylaxis to inhaled histamine in asthmatic subjects. , 1987, Journal of applied physiology.

[18]  J W Hershey,et al.  Structure of cDNAs Encoding Human Eukaryotic Initiation Factor 3 Subunits , 1997, The Journal of Biological Chemistry.

[19]  T. Cocks,et al.  Evidence that mechanisms dependent and independent of nitric oxide mediate endothelium‐dependent relaxation to bradykinin in human small resistance‐like coronary arteries , 1997, British journal of pharmacology.

[20]  W. Herr,et al.  Differential transcriptional activation by Oct-1 and Oct-2: Interdependent activation domains induce Oct-2 phosphorylation , 1990, Cell.

[21]  Bruno Amati,et al.  Phosphorylation‐dependent degradation of the cyclin‐dependent kinase inhibitor p27Kip1 , 1997, The EMBO journal.

[22]  James M. Roberts,et al.  Cloning of p27 Kip1 , a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals , 1994, Cell.

[23]  M. Roussel,et al.  Novel INK4 proteins, p19 and p18, are specific inhibitors of the cyclin D-dependent kinases CDK4 and CDK6 , 1995, Molecular and cellular biology.

[24]  P. Steeg,et al.  Cancer prognostics: Past, present and p27 , 1997, Nature Medicine.

[25]  M. Ewen,et al.  Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase CDK4. , 1993, Genes & development.

[26]  P. O'Byrne,et al.  The effect of indomethacin on exercise-induced bronchoconstriction and refractoriness after exercise. , 1986, The American review of respiratory disease.

[27]  A. Goldberg,et al.  Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules , 1994, Cell.

[28]  James M. Roberts,et al.  p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. , 1994, Genes & development.

[29]  W. Baumeister,et al.  A Subcomplex of the Proteasome Regulatory Particle Required for Ubiquitin-Conjugate Degradation and Related to the COP9-Signalosome and eIF3 , 1998, Cell.

[30]  R. Kraft,et al.  A novel protein complex involved in signal transduction possessing similarities to 26S proteasome subunits , 1998, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[31]  S. Elledge,et al.  The retinoblastoma protein associates with the protein phosphatase type 1 catalytic subunit. , 1993, Genes & development.

[32]  Minoru Yoshida,et al.  CRM1 is responsible for intracellular transport mediated by the nuclear export signal , 1997, Nature.

[33]  Toshiaki Tanaka,et al.  Transcription Factor E2F and Cyclin E-Cdk2 Complex Cooperate to Induce Chromosomal DNA Replication in Xenopus Oocytes* , 1998, The Journal of Biological Chemistry.

[34]  S. Coughlin Thrombin receptor function and cardiovascular disease. , 1994, Trends in cardiovascular medicine.

[35]  S. Moncada,et al.  Nitric oxide: physiology, pathophysiology, and pharmacology. , 1991, Pharmacological reviews.

[36]  S. Elledge,et al.  p57KIP2, a structurally distinct member of the p21CIP1 Cdk inhibitor family, is a candidate tumor suppressor gene. , 1995, Genes & development.

[37]  James M. Roberts,et al.  Cyclin E-CDK2 is a regulator of p27Kip1. , 1997, Genes & development.

[38]  S. Elledge,et al.  The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases , 1993, Cell.

[39]  K. Umesono,et al.  Localization, trafficking, and temperature-dependence of the Aequorea green fluorescent protein in cultured vertebrate cells. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[40]  C. Wahlestedt,et al.  Molecular cloning of a potential proteinase activated receptor. , 1994, Proceedings of the National Academy of Sciences of the United States of America.