Caveolin-1 Regulates the Antagonistic Pleiotropic Properties of Cellular Senescence through a Novel Mdm2/p53-Mediated Pathway

被引:91
|
作者
Bartholomew, Janine N. [1 ]
Volonte, Daniela [1 ]
Galbiati, Ferruccio [1 ]
机构
[1] Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15261 USA
关键词
PREMATURE SENESCENCE; HUMAN FIBROBLASTS; KINASE-ACTIVITY; P53; PROTEIN; IN-VITRO; EXPRESSION; CELLS; CANCER; GROWTH; GENES;
D O I
10.1158/0008-5472.CAN-08-2857
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
We show that caveolin-1 is a novel binding protein for Mdm2. After oxidative stress, caveolin-1 sequesters Mdm2 away from p53, leading to stabilization of p53 and up-regulation of p21(Waf1/Cip1) in human fibroblasts. Expression of a peptide corresponding to the Mdm2 binding domain of caveolin-1 is sufficient to up-regulate p53 and p21(Waf1/Cip1) protein expression and induce premature senescence. Oxidative stress-induced activation of the p53/p21(Waf1/Cip1) pathway and induction of premature senescence are compromised in caveolin-1 null mouse embryonic fibroblasts (MEF). We also show that reintroduction of caveolin-1 in oncogenic Ras (Ras(G12V))-transformed fibroblasts, which express residual levels of caveolin-1, is sufficient to promote cellular senescence. Moreover, caveolin-1 expression in MEFs is required for senescent fibroblast-induced stimulation of cell growth and tumorigenesis of both Ras(G12V)-transformed fibroblasts and MDA-MB-231 breast cancer epithelial cells both in vitro and in vivo. Thus, our results propose caveolin-1 as a key mediator of the antagonistic pleiotropic properties of cellular senescence. [Cancer Res 2009;69(7):2878-86]
引用
收藏
页码:2878 / 2886
页数:9
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