SHP-2 tyrosine phosphatase inhibits p73-dependent apoptosis and expression of a subset of p53 target genes induced by EGCG

被引:42
作者
Amin, A. R. M. Ruhul
Thakur, Vijay S.
Paul, Rajib K.
Feng, Gen Sheng
Qu, Cheng-Kui
Mukhtar, Hasan
Agarwal, Munna L. [1 ]
机构
[1] Case Western Reserve Univ, Dept Genet, Cleveland, OH 44106 USA
[2] Case Western Reserve Univ, Dept Hematol & Oncol, Cleveland, OH 44106 USA
[3] Burnham Inst, La Jolla, CA 92037 USA
[4] Univ Wisconsin, Madison, WI 53706 USA
关键词
green tea; MAPK pathway; mouse embryonic fibroblasts; transcriptional activation;
D O I
10.1073/pnas.0700642104
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Green tea polyphenol, epigallocatechin-3-gallate (EGCG) differentially regulates the cellular growth of cancer cells in a p53-dependent manner through apoptosis and/or cell cycle arrest. In an effort to further elucidate the mechanism of differential growth regulation by EGCG, we have investigated the role of the tyrosine phosphatase, SHP-2. Comparing the responses of mouse embryonic fibroblasts (MEFs), expressing either WT or functionally inactive/truncated SHP-2, we find that inactivation of SHP-2 remarkably sensitizes cells to EGCG-mediated killing. MEFs lacking functional SHP-2 undergo massive apoptosis upon treatment with EGCG. By comparing gene expression profiles, we have identified a set of transcriptional targets of p53 that are differentially modulated in cells undergoing apoptosis. Western blot and real-time PCR analyses of a select group of genes further confirm that the expression is SHP-2-dependent. Similar observations were made in MEFs lacking p53, confirming that the expression of these "p53 target genes" is p53-independent. In addition, EGCG treatment induced the expression of p73 mRNA and protein in both cell types, but not p63. Inactivation of p73 in cells expressing nonfunctional SHP-2 markedly inhibited apoptosis and p53 target gene expression. Although phosphorylation of JNK is differentially regulated by SHP2, it was found to be dispensable for EGCG-induced apoptosis and p53 target gene expression. Our results have identified SHP-2 as a negative regulator of EGCG-induced-apoptosis and have identified a subset of p53 target genes whose expression is paradoxically not mediated by p53 but by one of its family members, p73.
引用
收藏
页码:5419 / 5424
页数:6
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