| Autor: |
Weimin Li, Kotoshiba, Shuhei, Berthet, Cyril, Hilton, Mary Beth, Kaldis, Philipp |
| Předmět: |
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| Zdroj: |
Proceedings of the National Academy of Sciences of the United States of America; 1/13/2009, Vol. 106 Issue 2, p486-491, 6p, 3 Color Photographs, 2 Graphs |
| Abstrakt: |
The G[sub1]/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[sub1] to S-phase progression, we generated Cdk2[sup-/-]Cdk4[sup-/-]Rb[sup-/-] (TKO) mutant mice. TKO mice died at midgestation with major defects in the circulatory systems and displayed combined phenotypes of Rb[sup-/-] and Cdk2[sup-/-]Cdk4[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 Cdk2ICdk4 elicited a mechanism for the GuS regulation with increased levels of p27[supKiP1] binding to CdklI cyclin E complexes. Our work indicates that the G115 transition can be controlled in different ways depending on the situation, resembling a regulatory network. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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