Rb/Cdk2/Cdk4 triple mutant mice elicit an alternative mechanism for regulation of the G1/S transition

Weimin Li; Shuhei Kotoshiba; Cyril Berthet; Mary Beth Hilton; Philipp Kaldis

doi:10.1073/pnas.0804177106

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Rb/Cdk2/Cdk4 triple mutant mice elicit an alternative mechanism for regulation of the G1/S transition

Journal article

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Rb/Cdk2/Cdk4 triple mutant mice elicit an alternative mechanism for regulation of the G1/S transition

Weimin Li, Shuhei Kotoshiba, Cyril Berthet, Mary Beth Hilton and Philipp Kaldis

Proceedings of the National Academy of Sciences - PNAS, Vol.106(2), pp.486-491

01/13/2009

DOI: https://doi.org/10.1073/pnas.0804177106

Handle:

https://hdl.handle.net/2376/100878

PMCID: PMC2626729

PMID: 19129496

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Abstract

Cellular Senescence - genetics

Cell Proliferation

Cells, Cultured

Retinoblastoma Protein - deficiency

Mice, Knockout

Multiprotein Complexes - physiology

CDC2 Protein Kinase - metabolism

Cyclin-Dependent Kinase Inhibitor p27 - metabolism

G1 Phase

Animals

S Phase

Cyclin-Dependent Kinase 2 - deficiency

Hypoxia

Cyclin-Dependent Kinase 4 - deficiency

Fibroblasts - cytology

Mice

Cyclin E - metabolism

Interphase - genetics

The G(1)/S-phase transition is a well-toned switch in the mammalian cell cycle. Cdk2, Cdk4, and the rate-limiting tumor suppressor retinoblastoma protein (Rb) have been studied in separate animal models, but interactions between the kinases and Rb in vivo have yet to be investigated. To further dissect the regulation of the G(1) to S-phase progression, we generated Cdk2(-/-)Cdk4(-/-)Rb(-/-) (TKO) mutant mice. TKO mice died at midgestation with major defects in the circulatory systems and displayed combined phenotypes of Rb(-/-) and Cdk2(-/-)Cdk4(-/-) mutants. However, TKO mouse embryonic fibroblasts were not only resistant to senescence and became immortal but displayed enhanced S-phase entry and proliferation rates similar to wild type. These effects were more remarkable in hypoxic compared with normoxic conditions. Interestingly, depletion of the pocket proteins by HPV-E7 or p107/p130 shRNA in the absence of Cdk2/Cdk4 elicited a mechanism for the G(1)/S regulation with increased levels of p27(Kip1) binding to Cdk1/cyclin E complexes. Our work indicates that the G(1)/S transition can be controlled in different ways depending on the situation, resembling a regulatory network.

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Title: Rb/Cdk2/Cdk4 triple mutant mice elicit an alternative mechanism for regulation of the G1/S transition
Creators: Weimin Li - Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Building 560/22-56, 1050 Boyles Street, Frederick, MD 21702-1201, USA
Shuhei Kotoshiba
Cyril Berthet
Mary Beth Hilton
Philipp Kaldis
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.106(2), pp.486-491
Academic Unit: Biomedical Sciences, Department of
Publisher: United States
Grant note: Intramural NIH HHS
Identifiers: 99900546682401842
Language: English
Resource Type: Journal article