Combined loss of Cdk2 and Cdk4 results in embryonic lethality and Rb hypophosphorylation
Berthet, Cyril ; Klarmann, Kimberly D. ; Hilton, Mary Beth ; Suh, Hyung Chan ; Keller, Jonathan R. ; Kiyokawa, Hiroaki and Kaldis, Philipp LU
(2006)
In Developmental Cell
10(5).
p.563-573
- 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... (More)
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.
(Less)
- author
- Berthet, Cyril
; Klarmann, Kimberly D.
; Hilton, Mary Beth
; Suh, Hyung Chan
; Keller, Jonathan R.
; Kiyokawa, Hiroaki
and Kaldis, Philipp
LU
- publishing date
- 2006-05-01
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- CELLCYCLE, DEVBIO
- in
- Developmental Cell
- volume
- 10
- issue
- 5
- pages
- 11 pages
- publisher
- Cell Press
- external identifiers
-
- pmid:16678773
- scopus:33646528191
- ISSN
- 1534-5807
- DOI
- 10.1016/j.devcel.2006.03.004
- language
- English
- LU publication?
- no
- id
- 34bed6f2-07b2-461d-93ed-83cc0f20a140
- date added to LUP
- 2019-09-18 14:23:46
- date last changed
- 2024-04-16 20:40:48
@article{34bed6f2-07b2-461d-93ed-83cc0f20a140,
abstract = {{<p>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<sup>-/-</sup>Cdk4<sup>-/-</sup> 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<sup>-/-</sup>Cdk4<sup>-/-</sup> 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.</p>}},
author = {{Berthet, Cyril and Klarmann, Kimberly D. and Hilton, Mary Beth and Suh, Hyung Chan and Keller, Jonathan R. and Kiyokawa, Hiroaki and Kaldis, Philipp}},
issn = {{1534-5807}},
keywords = {{CELLCYCLE; DEVBIO}},
language = {{eng}},
month = {{05}},
number = {{5}},
pages = {{563--573}},
publisher = {{Cell Press}},
series = {{Developmental Cell}},
title = {{Combined loss of Cdk2 and Cdk4 results in embryonic lethality and Rb hypophosphorylation}},
url = {{http://dx.doi.org/10.1016/j.devcel.2006.03.004}},
doi = {{10.1016/j.devcel.2006.03.004}},
volume = {{10}},
year = {{2006}},
}