CARPs enhance p53 turnover by degrading 14-3-3σ and stabilizing MDM2

被引：30

作者：

Yang, Wensheng ^{[1
,2
,3
]}

Dicker, David T. ^{[1
,2
,3
]}

Chen, Jiandong ^{[4
]}

El-Deiry, Wafik S. ^{[1
,2
,3
]}

机构：

[1] Univ Penn, Sch Med, Lab Mol Oncol & Cell Cycle Regulat, Dept Med Hematol Oncol,Abramson Comprehens Canc C, Philadelphia, PA 19104 USA

[2] Univ Penn, Sch Med, Lab Mol Oncol & Cell Cycle Regulat, Dept Pharmacol & Genet,Abramson Comprehens Canc C, Philadelphia, PA 19104 USA

[3] Univ Penn, Sch Med, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA

[4] H Lee Moffitt Canc Ctr & Res Inst, Mol Oncol Program, Tampa, FL USA

来源：

CELL CYCLE | 2008年 / 7卷 / 05期

关键词：

CARPs; MDM2; p53; 14-3-3; sigma; MDMX; HIF1; alpha; IGF-1;

D O I：

10.4161/cc.7.5.5701

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：670 / 682

页数：13

共 52 条

[1] Induction of vascular endothelial growth factor by IGF-I in osteoblast-like cells is mediated by the PI3K signaling pathway through the hypoxia-inducible factor-2α [J].