Combined Loss of Cdk2 and Cdk4 Results in Embryonic Lethality and Rb Hypophosphorylation

Cyril Berthet, Kimberly D. Klarmann, Mary Beth Hilton, Hyung Chan Suh, Jonathan R. Keller, Hiroaki Kiyokawa, Philipp Kaldis*

*Corresponding author for this work

Research output: Contribution to journalArticle

121 Scopus citations

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 Cdk2-/-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.

Original languageEnglish (US)
Pages (from-to)563-573
Number of pages11
JournalDevelopmental Cell
Volume10
Issue number5
DOIs
StatePublished - May 1 2006

Keywords

  • CELLCYCLE
  • DEVBIO

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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    Berthet, C., Klarmann, K. D., Hilton, M. B., Suh, H. C., Keller, J. R., Kiyokawa, H., & Kaldis, P. (2006). Combined Loss of Cdk2 and Cdk4 Results in Embryonic Lethality and Rb Hypophosphorylation. Developmental Cell, 10(5), 563-573. https://doi.org/10.1016/j.devcel.2006.03.004