G1 control in mammalian cells

SUMMARY Cyclin-dependent kinases (Cdks) control the major cell cycle transitions in eukaryotic cells. On the basis of a variety of experiments where cyclin function either is impaired or enhanced, D-type cyclins as well as cyclins E and A have been linked to G1 and G1/S phase roles in mammalian cells. We therefore sought to determine if agents that block the G1/S phase transition do so at the level of regulating the Cdk activities associated with these cyclins. A variety of conditions that lead to G1 arrest were found to correlate with accumulation of G1-specific Cdk inhibitors, including treatment of fibroblasts with ionizing radiation, treatment of epithelial cells with TGF-β, treatment of HeLa cells with the drug lovastatin, and removal of essential growth factors from a variety of different cell types. Mechanistically, inhibition of Cdks was found to involve the stoichiometric binding of Cdk inhibitor proteins. p21Waf1/Cip1 was associated with DNA damage induced arrest while p27Kip1/p28Ick1 accumulated under a variety of antiproliferative conditions.

[1]  D. Beach,et al.  Population explosion in the cyclin family , 1991, Current Biology.

[2]  Chun-Ming Huang,et al.  SV40 large T antigen binds preferentially to an underphosphorylated member of the retinoblastoma susceptibility gene product family , 1989, Cell.

[3]  Anne Fernandez,et al.  Cyclin a is required for the onset of DNA replication in mammalian fibroblasts , 1991, Cell.

[4]  James M. Roberts,et al.  Human cyclin E, a new cyclin that interacts with two members of the CDC2 gene family , 1991, Cell.

[5]  S. Reed,et al.  Cyclin E/cdk2 and cyclin A/cdk2 kinases associate with p107 and E2F in a temporally distinct manner. , 1992, Genes & development.

[6]  Marc Vidal,et al.  A cDNA encoding a pRB-binding protein with properties of the transcription factor E2F , 1992, Cell.

[7]  C. Anderson,et al.  The retinoblastoma protein is phosphorylated on multiple sites by human cdc2. , 1991, The EMBO journal.

[8]  David M. Livingston,et al.  Functional interactions of the retinoblastoma protein with mammalian D-type cyclins , 1993, Cell.

[9]  J. Nevins,et al.  E2F: a link between the Rb tumor suppressor protein and viral oncoproteins. , 1992, Science.

[10]  C. Turck,et al.  Inhibition of CDK2 activity in vivo by an associated 20K regulatory subunit , 1993, Nature.

[11]  Steven K. Hanks,et al.  Identification and properties of an atypical catalytic subunit (p34PSK-J3/cdk4) for mammalian D type G1 cyclins , 1992, Cell.

[12]  R. Pepperkok,et al.  Cyclin A is required at two points in the human cell cycle. , 1992, The EMBO journal.

[13]  James M. Roberts,et al.  Formation and activation of a cyclin E-cdk2 complex during the G1 phase of the human cell cycle , 1992 .

[14]  David Beach,et al.  p21 is a universal inhibitor of cyclin kinases , 1993, Nature.

[15]  James M. Roberts,et al.  Negative regulation of G1 in mammalian cells: inhibition of cyclin E-dependent kinase by TGF-beta. , 1993, Science.

[16]  Phang-lang Chen,et al.  Phosphorylation of the retinoblastoma gene product is modulated during the cell cycle and cellular differentiation , 1989, Cell.

[17]  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.

[18]  T. Hunter,et al.  Cyclin-dependent kinases: a new cell cycle motif? , 1991, Trends in cell biology.

[19]  G. Hannon,et al.  Isolation of the Rb-related p130 through its interaction with CDK2 and cyclins. , 1993, Genes & development.

[20]  S. Reed,et al.  The role of p34 kinases in the G1 to S-phase transition. , 1992, Annual review of cell biology.

[21]  S. Reed,et al.  Altered regulation of G1 cyclins in senescent human diploid fibroblasts: accumulation of inactive cyclin E-Cdk2 and cyclin D1-Cdk2 complexes. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

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

[23]  D. Fesquet,et al.  Cyclin A is required in S phase in normal epithelial cells. , 1992, Biochemical and biophysical research communications.

[24]  James M. Roberts,et al.  Cyclin-dependent regulation of G1 in mammalian fibroblasts. , 1993, Science.

[25]  S. Reed,et al.  Association of human cyclin E with a periodic G1-S phase protein kinase. , 1992, Science.

[26]  D. Livingston,et al.  The retinoblastoma-susceptibility gene product becomes phosphorylated in multiple stages during cell cycle entry and progression. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[27]  D. Lew,et al.  A proliferation of cyclins. , 1992, Trends in cell biology.

[28]  S. Reed,et al.  Isolation of three novel human cyclins by rescue of G1 cyclin (cln) function in yeast , 1991, Cell.

[29]  M. Ewen,et al.  Inhibition of cell proliferation by p107, a relative of the retinoblastoma protein. , 1993, Genes & development.

[30]  S. Shurtleff,et al.  Overexpression of mouse D-type cyclins accelerates G1 phase in rodent fibroblasts. , 1993, Genes & development.

[31]  M. Vidal,et al.  The retinoblastoma protein binds to a family of E2F transcription factors , 1993, Molecular and cellular biology.

[32]  M. Pagano,et al.  Cyclin D1 is a nuclear protein required for cell cycle progression in G1. , 1993, Genes & development.

[33]  Tony Hunter,et al.  Human cyclin A is adenovirus E1A-associated protein p60 and behaves differently from cyclin B , 1990, Nature.

[34]  M. Ewen,et al.  Molecular cloning, chromosomal mapping, and expression of the cDNA for p107, a retinoblastoma gene product-related protein , 1991, Cell.

[35]  R. Weinberg,et al.  Regulation of retinoblastoma protein functions by ectopic expression of human cyclins , 1992, Cell.

[36]  C. Lehner,et al.  Cyclin E controls S phase progression and its down-regulation during Drosophila embryogenesis is required for the arrest of cell proliferation , 1994, Cell.

[37]  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.

[38]  J. Trent,et al.  WAF1, a potential mediator of p53 tumor suppression , 1993, Cell.

[39]  Stephen J. Elledge,et al.  p53-dependent inhibition of cyclin-dependent kinase activities in human fibroblasts during radiation-induced G1 arrest , 1994, Cell.

[40]  J. Little,et al.  Effect of confluent holding on potentially lethal damage repair, cell cycle progression, and chromosomal aberrations in human normal and ataxia-telangiectasia fibroblasts. , 1985, Radiation research.

[41]  E. Harlow,et al.  The retinoblastoma protein is phosphorylated during specific phases of the cell cycle , 1989, Cell.

[42]  W. Lee,et al.  Retinoblastoma cancer suppressor gene product is a substrate of the cell cycle regulator cdc2 kinase. , 1991, The EMBO journal.

[43]  R. Weinberg,et al.  Physical interaction of the retinoblastoma protein with human D cyclins , 1993, Cell.

[44]  A. Arnold,et al.  A novel cyclin encoded by a bcl1-linked candidate oncogene , 1991, Nature.

[45]  L. Hengst,et al.  A novel inhibitor of cyclin-Cdk activity detected in transforming growth factor beta-arrested epithelial cells , 1994, Molecular and cellular biology.

[46]  A. Yen,et al.  Cell cycle-dependent regulation of phosphorylation of the human retinoblastoma gene product. , 1989, Science.

[47]  Kathleen L. Gould,et al.  Tyrosine phosphorylation of the fission yeast cdc2+ protein kinase regulates entry into mitosis , 1989, Nature.

[48]  Peggy J. Farnham,et al.  Expression cloning of a cDNA encoding a retinoblastoma-binding protein with E2F-like properties , 1992, Cell.

[49]  Y. Xiong,et al.  Growth-regulated expression of D-type cyclin genes in human diploid fibroblasts. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[50]  M. Gossen,et al.  Acceleration of the G1/S phase transition by expression of cyclins D1 and E with an inducible system. , 1994, Molecular and cellular biology.

[51]  B. Futcher,et al.  Human D-type cyclin , 1991, Cell.

[52]  L. Hengst,et al.  A cell cycle-regulated inhibitor of cyclin-dependent kinases. , 1994, Proceedings of the National Academy of Sciences of the United States of America.