Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 104, Issue 13, Pages 5419-5424Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0700642104
Keywords
green tea; MAPK pathway; mouse embryonic fibroblasts; transcriptional activation
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Funding
- NCI NIH HHS [CA78809, R01 CA098916, R01 CA078809, R01 CA98916, CA101039, R01 CA101039] Funding Source: Medline
- NIDDK NIH HHS [DK065303, P50 DK065303] Funding Source: Medline
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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.
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