Combined Loss of Cdk2 and Cdk4 Results in Embryonic Lethality and Rb Hypophosphorylation
Mice, Knockout
0301 basic medicine
0303 health sciences
Papillomavirus E7 Proteins
Cyclin-Dependent Kinase 2
Cyclin-Dependent Kinase 4
DEVBIO
CELLCYCLE
Oncogene Proteins, Viral
Fibroblasts
Embryo, Mammalian
Retinoblastoma Protein
E2F Transcription Factors
Hematopoiesis
Mice, Inbred C57BL
Mice
03 medical and health sciences
Phenotype
Animals
Gene Silencing
Phosphorylation
Cells, Cultured
Developmental Biology
Cell Proliferation
DOI:
10.1016/j.devcel.2006.03.004
Publication Date:
2006-05-09T11:13:20Z
AUTHORS (7)
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.
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