Antagonism of p53-dependent apoptosis by mitogen signals.
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-xL, 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+.
Hong
M
M
Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan, Republic of China.
Lai
M D
MD
Lin
Y S
YS
Lai
M Z
MZ
D000818:Animals; D017209:Apoptosis; D000001:Calcimycin / Q000494:pharmacology; D002461:Cell Line, Transformed; D002945:Cisplatin / Q000494:pharmacology; D006801:Humans; D007476:Ionophores / Q000494:pharmacology; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases; D008934:Mitogens / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
C494826:BAX protein, human; C494811:BCL2L1 protein, human; C494827:Bax protein, mouse; C494812:Bcl2l1 protein, mouse; D007476:Ionophores; D008934:Mitogens; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D000001:Calcimycin; D011494:Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D013755:Tetradecanoylphorbol Acetate; D002945:Cisplatin