Phospholipase D elevates the level of MDM2 and suppresses DNA damage-induced increases in p53.
Phospholipase D (PLD) has been reported to generate survival signals that prevent apoptosis induced by serum withdrawal. We have now found that elevated expression of PLD also suppresses DNA damage-induced apoptosis. Since DNA damage-induced apoptosis is often mediated by p53, we examined the effect of elevated PLD expression on the regulation of p53 stabilization. We report here that PLD suppresses DNA damage-induced increases in p53 stabilization in cells where PLD has been shown to provide a survival signal. Elevated expression of PLD also led to increased expression of the p53 E3 ubiquitin ligase MDM2 and increased turnover of p53. PLD1-stimulated increases in MDM2 expression and suppression of p53 activation were blocked by inhibition of mTOR and the mitogen-activated protein kinase pathway. Although PLD did not activate the phosphatidylinositol 3-kinase (PI3K)/Akt survival pathway activate the basal levels of PI3K activity were partially required for PLD1-induced increases in MDM2. These data provide evidence that survival signals generated by PLD involve suppression of the p53 response pathway.
Hui
Li
L
Department of Biological Sciences, Hunter College of the City University of New York, 695 Park Ave., New York, NY 10021, USA.
Abbas
Tarek
T
Pielak
Rafal M
RM
Joseph
Troy
T
Bargonetti
Jill
J
Foster
David A
DA
D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D004249:DNA Damage; D006207:Half-Life; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D009687:Nuclear Proteins / Q000032:analysis / Q000096:biosynthesis; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010739:Phospholipase D / Q000502:physiology*; D011494:Protein Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000096:biosynthesis; D051736:Proto-Oncogene Proteins c-mdm2; D051381:Rats; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D020928:Mitogen-Activated Protein Kinases; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D010739:Phospholipase D; D011494:Protein Kinases; D011518:Proto-Oncogene Proteins; D051736:Proto-Oncogene Proteins c-mdm2; D058570:TOR Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53; C497208:Mdm2 protein, rat; C546845:mTOR protein, rat; C106801:phospholipase D1