Cdk2 is dispensable for cell cycle inhibition and tumor suppression mediated by p27(Kip1) and p21(Cip1).

p27(Kip1) and p21(Cip1) are thought to suppress tumor growth and prevent cell cycle progression by inhibiting Cdk2-cyclin E/A kinases. Since Cdk2 is dispensable for mitotic cell division, we analyzed the activity of these inhibitors in Cdk2-deficient cells. Ectopic expression of p27(Kip1) or p21(Cip1) efficiently inhibits cell cycle progression of Cdk2(-/-) fibroblasts. Loss of p27(Kip1) or p21(Cip1) confers similar proliferative advantages to Cdk2(+/+) and Cdk2(-/-) cells. Moreover, Cdk2 is dispensable for p21(Cip1)-induced cell cycle arrest after DNA damage. Finally, ablation of Cdk2 in p27(Kip1) null mice does not suppress their phenotypic defects, including development of pituitary tumors. These results indicate that Cdk2 is not an essential target for p27(Kip1) and p21(Cip1) in cell cycle inhibition and tumor suppression.

[1]  C. Cordon-Cardo,et al.  p27 as a target for cancer therapeutics. , 2003, Cancer cell.

[2]  J. Massagué,et al.  Differential Interaction of the Cyclin-dependent Kinase (Cdk) Inhibitor p27Kip1 with Cyclin A-Cdk2 and Cyclin D2-Cdk4* , 1997, The Journal of Biological Chemistry.

[3]  Pierre Dubus,et al.  Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice , 2003, Nature Genetics.

[4]  Pierre Dubus,et al.  Wide spectrum of tumors in knock‐in mice carrying a Cdk4 protein insensitive to INK4 inhibitors , 2001, The EMBO journal.

[5]  M. Serrano,et al.  Tumor susceptibility of p21(Waf1/Cip1)-deficient mice. , 2001, Cancer research.

[6]  Nobuyuki Shishido,et al.  Mice Lacking p27 Kip1 Display Increased Body Size, Multiple Organ Hyperplasia, Retinal Dysplasia, and Pituitary Tumors , 1996, Cell.

[7]  Tony Hunter,et al.  p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21 , 1994, Cell.

[8]  G. Hannon,et al.  Differential effects by the p21 CDK inhibitor on PCNA-dependent DNA replication and repair , 1994, Nature.

[9]  G. Hannon,et al.  The p21 inhibitor of cyclin-dependent kinases controls DNA replication by interaction with PCNA , 1994, Nature.

[10]  T. Kwon,et al.  Identification of cdk2 binding sites on the p27Kip1 cyclin-dependent kinase inhibitor , 1998, Oncogene.

[11]  S. Elledge,et al.  Inhibition of cyclin-dependent kinases by p21. , 1995, Molecular biology of the cell.

[12]  Shengjun Ren,et al.  Cyclin C/Cdk3 Promotes Rb-Dependent G0 Exit , 2004, Cell.

[13]  P. Kaldis,et al.  Cdk2 Knockout Mice Are Viable , 2003, Current Biology.

[14]  S. Lowe,et al.  Intrinsic tumour suppression , 2004, Nature.

[15]  J. Massagué,et al.  Cell-cycle inhibition by independent CDK and PCNA binding domains in p21Cip1 , 1995, Nature.

[16]  C. Prives,et al.  P53 and Prognosis New Insights and Further Complexity , 2005, Cell.

[17]  K. Akashi,et al.  Mouse Development and Cell Proliferation in the Absence of D-Cyclins , 2004, Cell.

[18]  James Brugarolas,et al.  Radiation-induced cell cycle arrest compromised by p21 deficiency , 1995, Nature.

[19]  K. Nakayama,et al.  Cip/Kip cyclin‐dependent kinase inhibitors: brakes of the cell cycle engine during development , 1998, BioEssays : news and reviews in molecular, cellular and developmental biology.

[20]  James M. Roberts,et al.  The p21Cip1 and p27Kip1 CDK ‘inhibitors’ are essential activators of cyclin D‐dependent kinases in murine fibroblasts , 1999, The EMBO journal.

[21]  M. Pagano.  Control of DNA synthesis and mitosis by the Skp2-p27-Cdk1/2 axis. , 2004, Molecular cell.

[22]  M. Kirschner,et al.  Separate domains of p21 involved in the inhibition of Cdk kinase and PCNA , 1995, Nature.

[23]  James M. Roberts,et al.  The murine gene p27Kip1 is haplo-insufficient for tumour suppression , 1998, Nature.

[24]  J. Harper,et al.  A premature-termination mutation in the Mus musculus cyclin-dependent kinase 3 gene. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[25]  Bernard Ducommun,et al.  p21 binding to PCNA causes G1 and G2 cell cycle arrest in p53-deficient cells , 1998, Oncogene.

[26]  K. Manova-Todorova,et al.  Enhanced Growth of Mice Lacking the Cyclin-Dependent Kinase Inhibitor Function of p27 Kip1 , 1996, Cell.

[27]  A. Levine,et al.  Analysis of wild-type and mutant p21WAF-1 gene activities , 1996, Molecular and cellular biology.

[28]  James M. Roberts,et al.  A Syndrome of Multiorgan Hyperplasia with Features of Gigantism, Tumorigenesis, and Female Sterility in p27 Kip1 -Deficient Mice , 1996, Cell.

[29]  Steven F Dowdy,et al.  Cip/Kip proteins: more than just CDKs inhibitors. , 2004, Genes & development.

[30]  J. LaBaer,et al.  New functional activities for the p21 family of CDK inhibitors. , 1997, Genes & development.

[31]  M. Malumbres,et al.  Cell cycle deregulation: a common motif in cancer. , 2003, Progress in cell cycle research.

[32]  Michele Pagano,et al.  Deregulated degradation of the cdk inhibitor p27 and malignant transformation. , 2003, Seminars in cancer biology.

[33]  James M. Roberts,et al.  CDK inhibitors: positive and negative regulators of G1-phase progression. , 1999, Genes & development.

[34]  Stephen J. Elledge,et al.  Mice Lacking p21 CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control , 1995, Cell.

[35]  E. Lam,et al.  Inhibition of the Phosphoinositide 3-Kinase Pathway Induces a Senescence-like Arrest Mediated by p27Kip1 * , 2000, The Journal of Biological Chemistry.

[36]  Pierre Dubus,et al.  Mammalian Cells Cycle without the D-Type Cyclin-Dependent Kinases Cdk4 and Cdk6 , 2004, Cell.

[37]  Tohru Natsume,et al.  Skp2-mediated degradation of p27 regulates progression into mitosis. , 2004, Developmental cell.

[38]  S. Reed,et al.  Ratchets and clocks: the cell cycle, ubiquitylation and protein turnover , 2003, Nature Reviews Molecular Cell Biology.