期刊
CELL CYCLE
卷 7, 期 5, 页码 670-682出版社
LANDES BIOSCIENCE
DOI: 10.4161/cc.7.5.5701
关键词
CARPs; MDM2; p53; 14-3-3 sigma; MDMX; HIF1 alpha; IGF-1
类别
资金
- NCI NIH HHS [CA-97100, CA-105008, CA-75138, CA-98101] Funding Source: Medline
CARP1 and CARP2 proteins (CARPs) are E3 ligases that target p53 as well as phospho-p53 for degradation. Because MDM2 is a critical regulator of p53 turnover, we investigated and found that CARPs associate with MDM2. We provide evidence that CARPs stabilize MDM2 by inhibiting MDM2 self-ubiquitination. CARPs together with MDM2 enhance p53 degradation, thereby inhibiting p53-mediated cell death. CARP protein levels correlate with MDM2 levels including under hypoxia where both are reduced. CARP2 was found to target 14-3-3 sigma for degradation, leading to MDM2 stabilization. MDMX, a homolog of MDM2, is not absolutely required for MDM2 stabilization by CARPs, although overexpression of CARP2 enhances MDM2/MDMX interaction. Taken together, our study identifies novel mechanisms by which CARP proteins regulate the p53 signaling pathway.
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