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Molecular and Cellular Biology, July 2004, p. 5677-5686, Vol. 24, No. 13
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.13.5677-5686.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Phospholipase D Elevates the Level of MDM2 and Suppresses DNA Damage-Induced Increases in p53

Li Hui, Tarek Abbas, Rafal M. Pielak, Troy Joseph, Jill Bargonetti, and David A. Foster*

Department of Biological Sciences, Hunter College of the City University of New York, New York, New York 10021

Received 13 December 2003/ Returned for modification 6 February 2004/ Accepted 6 March 2004

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.

* Corresponding author. Mailing address: Department of Biological Sciences, Hunter College of the City University of New York, 695 Park Ave., New York, NY 10021. Phone: (212) 772-4075. Fax: (212) 772-5227. E-mail: foster{at}genectr.hunter.cuny.edu.

Molecular and Cellular Biology, July 2004, p. 5677-5686, Vol. 24, No. 13
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.13.5677-5686.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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