SHP-2 tyrosine phosphatase inhibits p73-dependent apoptosis and expression of a subset of p53 target genes induced by EGCG
- 27 March 2007
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 104 (13), 5419-5424
- https://doi.org/10.1073/pnas.0700642104
Abstract
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.Keywords
This publication has 46 references indexed in Scilit:
- Differential contribution of Puma and Noxa in dual regulation of p53-mediated apoptotic pathwaysThe EMBO Journal, 2006
- Role of p53 Up-regulated Modulator of Apoptosis and Phosphorylated Akt in Melanoma Cell Growth, Apoptosis, and Patient SurvivalCancer Research, 2006
- FKHRL1-mediated expression of Noxa and Bim induces apoptosis via the mitochondria in neuroblastoma cellsCell Death & Differentiation, 2006
- Green tea and its polyphenolic catechins: Medicinal uses in cancer and noncancer applicationsLife Sciences, 2006
- TP53INP1 is a novel p73 target gene that induces cell cycle arrest and cell death by modulating p73 transcriptional activityOncogene, 2005
- Regulation of the p73 protein stability and degradationBiochemical and Biophysical Research Communications, 2005
- Green tea extract and (−)‐epigallocatechin‐3‐gallate, the major tea catechin, exert oxidant but lack antioxidant activitiesThe FASEB Journal, 2005
- A role for SHPS-1/SIRPα1 in IL-1β- and TNFα-dependent signalingOncogene, 2002
- Live or let die: the cell's response to p53Nature Reviews Cancer, 2002
- Analysis of Molecular Interactions of the p53-Family p51(p63) Gene Products in a Yeast Two-Hybrid System: Homotypic and Heterotypic Interactions and Association with p53-Regulatory FactorsBiochemical and Biophysical Research Communications, 2001