Pyk2抑制p53适应性和内在机制促进细胞增殖和生存。
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Lim圣,米勒问,南乔,陈XL Lim Y,施弗弟弟
Pyk2抑制p53适应性和内在机制促进细胞增殖和生存。
J生物化学杂志。2010年1月15日,285 (3):1743 - 53。doi: 10.1074 / jbc.M109.064212。Epub 2009年10月30日。
- PubMed ID
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19880522 (在PubMed]
- 文摘
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Pyk2是胞质酪氨酸激酶相关粘着斑激酶(FAK)。补偿Pyk2表达式在FAK损失发生在老鼠。然而,的影响Pyk2老年病仍不清楚。先前的研究表明,nuclear-localized FAK促进细胞增殖和生存通过FAK丰贸domain-enhanced p53肿瘤抑制退化(Lim s T。陈,x L。Lim, Y。汉森,d。签证官,T . T。Howerton, K。Larocque, N。费舍尔,s . J。施弗,D D。大型、d细胞(2008)摩尔。29日,9-22)。在这里,我们表明,FAK击倒触发激活p53和G(1)细胞周期阻滞在人类脐静脉内皮细胞后4天。 However, by 7 days elevated Pyk2 expression occurred with a reduction in p53 levels and the release of the G(1) block under conditions of continued FAK knockdown. To determine whether Pyk2 regulates p53, experiments were performed in FAK(-/-)p21(-/-) mouse embryo fibroblasts expressing endogenous Pyk2 and in ID8 ovarian carcinoma cells expressing both Pyk2 and FAK. In both cell lines, Pyk2 knockdown increased p53 levels and inhibited cell proliferation associated with G(1) cell cycle arrest. Pyk2 FERM domain re-expression was sufficient to reduce p53 levels and promote increased BrdUrd incorporation. Pyk2 FERM promoted Mdm2-dependent p53 ubiquitination. Pyk2 FERM effects on p53 were blocked by proteasomal inhibition or mutational-inactivation of Pyk2 FERM nuclear localization. Staurosporine stress of ID8 cells promoted endogenous Pyk2 nuclear accumulation and enhanced Pyk2 binding to p53. Pyk2 knockdown potentiated ID8 cell death upon staurosporine addition. Moreover, Pyk2 FERM expression in human fibroblasts upon FAK knockdown prevented cisplatin-mediated apoptosis. Our studies demonstrate that nuclear Pyk2 functions to limit p53 levels, thus facilitating cell growth and survival in a kinase-independent manner.