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Combined loss of Cdk2 and Cdk4 results in embryonic lethality and Rb hypophosphorylation

  1. Author:
    Berthet, C.
    Klarmann, K. D.
    Hilton, M. B.
    Suh, H. C.
    Keller, J. R.
    Kiyokawa, H.
    Kaldis, P.

  2. Author Address

    NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA. NCI, Basic Res Program, Sci Applicat Int Corp, Frederick, MD 21702 USA. Northwestern Univ, Feinberg Sch Med, Dept Mol Pharmacol & Biol Chem, Chicago, IL 60611 USA Kaldis, P, NCI, Mouse Canc Genet Program, Bldg 560-22-56, Frederick, MD 21702 USA
    1. Year: 2006
    2. Date: MAY
  2. Journal: Developmental Cell
    1. 10
    2. 5
    3. Pages: 563-573
  4. Type of Article: Article
  1. Abstract:

    Mouse knockouts of Cdk2 and Cdk4 have demonstrated that, individually, these genes are not essential for viability. To investigate whether there is functional redundancy, we have generated double knockout (DKO) mice. Cdk2(-/-) Cdk4(-/-) DKOs die during embryogenesis around E15 as a result of heart defects. We observed a gradual decrease of Retinoblastoma protein (Rb) phosphorylation and reduced expression of E2F-target genes, like Cdc2 and cyclin A2, during embryogenesis and in embryonic fibroblasts (MEFs). DKO MEFs are characterized by a decreased proliferation rate, impaired S phase entry, and premature senescence. HPV-E7-mediated inactivation of Rb restored normal expression of E2F-inducible genes, senescence, and proliferation in DKO MEFs. In contrast, loss of p27 did not rescue CdkZ(-/-) Cdk4(-/-) phenotypes. Our results demonstrate that Cdk2 and Cdk4 cooperate to phosphorylate Rb in vivo and to couple the G1/S phase transition to mitosis via E2F-dependent regulation of gene expression

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External Sources

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  2. DOI: 10.1016/j.devcel.2006.03.004
  3. View record in Web of Science®
  4. WOS: 000237648800007

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