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

doi:10.1016/j.devcel.2006.03.004

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

Pharmacology

Research output: Contribution to journal › Article › peer-review

129 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 language	English (US)
Pages (from-to)	563-573
Number of pages	11
Journal	Developmental Cell
Volume	10
Issue number	5
DOIs	https://doi.org/10.1016/j.devcel.2006.03.004
State	Published - May 2006

Keywords

CELLCYCLE
DEVBIO

ASJC Scopus subject areas

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

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10.1016/j.devcel.2006.03.004

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@article{8dac480635744a46bf470fe1fca07c6f,

title = "Combined Loss of Cdk2 and Cdk4 Results in Embryonic Lethality and Rb Hypophosphorylation",

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.",

keywords = "CELLCYCLE, DEVBIO",

author = "Cyril Berthet and Klarmann, {Kimberly D.} and Hilton, {Mary Beth} and Suh, {Hyung Chan} and Keller, {Jonathan R.} and Hiroaki Kiyokawa and Philipp Kaldis",

note = "Funding Information: The authors thank Nancy Jenkins and Neal Copeland for advice, discussion, reagents, and support. We also thank Barbara Shankle and Carlton Briggs for technical help; Karen Stull, Matt McCollum, and Angie Smith for animal care; Kathleen Noer and Roberta Matthai for FACS analysis; and Keith Rogers, Roberta Smith, Jen Matta, and Miriam Anver ( http://web/rtp/lasp/phl/ ) for the analysis of mouse pathology. We are grateful to Brad St. Croix and Ira Daar for providing equipment and reagents, and to Karl M{\"u}nger for HPV-E7 mutants. We really appreciated the help of Debbie Hodge, Shyam Sharan, Eiman Aleem, Karlyne Reilly, Esta Sterneck, Lino Tessarollo, Enzo Coppola, Terry Yamaguchi, and the Kaldis lab for discussions and collaboration. We are thankful to Deborah Morrison, Shyam Sharan, V.C. Padmakumar, Weimin Li, Jean-Pierre Magaud, Jacques Samarut, Neil Segil, and Neal Copeland for comments on the manuscript. C.B. dedicates this paper to Sophie for her support and to Manon, Agathe, and Emeric. This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. ",

year = "2006",

month = may,

doi = "10.1016/j.devcel.2006.03.004",

language = "English (US)",

volume = "10",

pages = "563--573",

journal = "Developmental Cell",

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T1 - Combined Loss of Cdk2 and Cdk4 Results in Embryonic Lethality and Rb Hypophosphorylation

AU - Berthet, Cyril

AU - Klarmann, Kimberly D.

AU - Hilton, Mary Beth

AU - Suh, Hyung Chan

AU - Keller, Jonathan R.

AU - Kiyokawa, Hiroaki

AU - Kaldis, Philipp

N1 - Funding Information: The authors thank Nancy Jenkins and Neal Copeland for advice, discussion, reagents, and support. We also thank Barbara Shankle and Carlton Briggs for technical help; Karen Stull, Matt McCollum, and Angie Smith for animal care; Kathleen Noer and Roberta Matthai for FACS analysis; and Keith Rogers, Roberta Smith, Jen Matta, and Miriam Anver ( http://web/rtp/lasp/phl/ ) for the analysis of mouse pathology. We are grateful to Brad St. Croix and Ira Daar for providing equipment and reagents, and to Karl Münger for HPV-E7 mutants. We really appreciated the help of Debbie Hodge, Shyam Sharan, Eiman Aleem, Karlyne Reilly, Esta Sterneck, Lino Tessarollo, Enzo Coppola, Terry Yamaguchi, and the Kaldis lab for discussions and collaboration. We are thankful to Deborah Morrison, Shyam Sharan, V.C. Padmakumar, Weimin Li, Jean-Pierre Magaud, Jacques Samarut, Neil Segil, and Neal Copeland for comments on the manuscript. C.B. dedicates this paper to Sophie for her support and to Manon, Agathe, and Emeric. This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research.

PY - 2006/5

Y1 - 2006/5

N2 - 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.

AB - 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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AN - SCOPUS:33646528191

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JO - Developmental Cell

JF - Developmental Cell

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ER -

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

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