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Antagonism of p53-dependent Apoptosis by Mitogen Signals¹

Institutes of Molecular Biology [M. H., M-Z. L.] and Biomedical Science [Y-S. L.], Academia Sinica, Taipei 11529; Department of Biochemistry, National Cheng-Kung University, Tainan 70101 [M-D. L.]; Graduate Institute of Microbiology and Immunology, National Yang-Ming University, Taipei 11221 [M-Z. L.]; and Graduate Institute of Immunology, National Taiwan University, Taipei 10002 [M-Z. L.], Taiwan, Republic of China

p53-mediated apoptosis is antagonized by growth factor stimulation. Here, we show that p53-dependent cell death induced by DNA damage was effectively prevented by mitogen activation. The levels of Bcl-2, Bcl-x_L, and Bax were not altered by cisplatin treatment and mitogen rescue. Instead, the protection against p53-regulated apoptosis was mediated by at least three distinct signaling pathways. Either phosphatidylinositol (PI) 3-kinase or mitogen-activated protein kinase kinase (MEK) antagonized p53-induced apoptosis, and an additive preventive effect was observed when both kinases were activated. However, the combination of PI 3-kinase and MEK was not sufficient to completely prevent apoptosis induced by DNA damage. Mitogen activation further suppressed cisplatin-induced p53 expression, and the inhibition was mainly dependent on the Ca²⁺ pathway. Our results demonstrate that effective antagonism of p53-dependent apoptosis by mitogenic activation requires the presence of multiple signal pathways, including PI 3-kinase, MEK, and Ca²⁺.

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