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

Li, Weimin ; Kotoshiba, Shuhei ; Berthet, Cyril ; Hilton, Mary Beth and Kaldis, Philipp LU orcid (2009) In Proceedings of the National Academy of Sciences of the United States of America 106(2). p.486-491
Abstract

The G1/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 G1 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... (More)

The G1/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 G1 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 G1/S regulation with increased levels of p27Kip1 binding to Cdk1/cyclin E complexes. Our work indicates that the G1/S transition can be controlled in different ways depending on the situation, resembling a regulatory network.

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author
; ; ; and
publishing date
type
Contribution to journal
publication status
published
keywords
Cell cycle, p27, Retinoblastoma protein, Skp2
in
Proceedings of the National Academy of Sciences of the United States of America
volume
106
issue
2
pages
6 pages
publisher
National Academy of Sciences
external identifiers
  • pmid:19129496
  • scopus:58849151285
ISSN
0027-8424
DOI
10.1073/pnas.0804177106
language
English
LU publication?
no
id
9fe5126d-a479-4ebd-8689-f4632cbb37df
date added to LUP
2019-09-18 14:11:20
date last changed
2024-02-15 21:39:20
@article{9fe5126d-a479-4ebd-8689-f4632cbb37df,
  abstract     = {{<p>The G<sub>1</sub>/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<sub>1</sub> to S-phase progression, we generated Cdk2<sup>-/-</sup>Cdk4<sup>-/-</sup>Rb<sup>-/-</sup> (TKO) mutant mice. TKO mice died at midgestation with major defects in the circulatory systems and displayed combined phenotypes of Rb<sup>-/-</sup> and Cdk2 <sup>-/-</sup>Cdk4<sup>-/-</sup> 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<sub>1</sub>/S regulation with increased levels of p27<sup>Kip1</sup> binding to Cdk1/cyclin E complexes. Our work indicates that the G<sub>1</sub>/S transition can be controlled in different ways depending on the situation, resembling a regulatory network.</p>}},
  author       = {{Li, Weimin and Kotoshiba, Shuhei and Berthet, Cyril and Hilton, Mary Beth and Kaldis, Philipp}},
  issn         = {{0027-8424}},
  keywords     = {{Cell cycle; p27; Retinoblastoma protein; Skp2}},
  language     = {{eng}},
  month        = {{01}},
  number       = {{2}},
  pages        = {{486--491}},
  publisher    = {{National Academy of Sciences}},
  series       = {{Proceedings of the National Academy of Sciences of the United States of America}},
  title        = {{Rb/Cdk2/Cdk4 triple mutant mice elicit an alternative mechanism for regulation of the G<sub>1</sub>/S transition}},
  url          = {{http://dx.doi.org/10.1073/pnas.0804177106}},
  doi          = {{10.1073/pnas.0804177106}},
  volume       = {{106}},
  year         = {{2009}},
}