期刊
MOLECULAR CELL
卷 29, 期 1, 页码 9-22出版社
CELL PRESS
DOI: 10.1016/j.molcel.2007.11.031
关键词
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资金
- NCI NIH HHS [R29 CA075240, R01 CA102310-05, CA87652, R01 CA087038, R01 CA075240-11, R01 CA102310, CA102310, CA87038, R01 CA075240, K01 CA087652, CA75240, R01 CA087038-05] Funding Source: Medline
- NCRR NIH HHS [C06 RR016490, C06RR16490] Funding Source: Medline
FAK is known as an integrin- and growth factor-associated tyrosine kinase promoting cell motility. Here we show that, during mouse development, FAK inactivation results in p53- and p21-dependent mesodermal cell growth arrest. Reconstitution of primary FAK(-/-)p21(-/-) fibroblasts revealed that FAK, in a kinase-independent manner, facilitates p53 turnover via enhanced Mdm2-dependent p53 ubiquitination. p53 inactivation by FAK required FAK FERM F1 lobe binding to p53, FERM F2 lobe-mediated nuclear localization, and FERM F3 lobe for connections to Mdm2 and proteasomal degradation. Staurosporine or loss of cell adhesion enhanced FERM-dependent FAK nuclear accumulation. In primary human cells, FAK knockdown raised p53-p21 levels and slowed cell proliferation but did not cause apoptosis. Notably, FAK knockdown plus cisplatin triggered p53-dependent cell apoptosis, which was rescued by either full-length FAK or FAK FERM re-expression. These studies define a scaffolding role for nuclear FAK in facilitating cell survival through enhanced p53 degradation under conditions of cellular stress.
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