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Phospholipase D elevates the level of MDM2 and suppresses DNA damage-induced increases in p53

Li Hui1, Tarek Abbas, Rafal M Pielak

  • 1Department of Biological Sciences, Hunter College of the City University of New York, 695 Park Ave., New York, NY 10021, USA.

Molecular and Cellular Biology
|June 17, 2004
PubMed

Insights

Phospholipase D (PLD) suppresses apoptosis from DNA damage by inhibiting p53 stabilization. This involves increased MDM2 expression, leading to faster p53 turnover, suggesting PLD survival signals target the p53 pathway.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Phospholipase D (PLD) is known to generate survival signals preventing apoptosis from serum withdrawal.
  • DNA damage-induced apoptosis is a critical cellular process often regulated by the p53 tumor suppressor protein.

Purpose of the Study:

  • To investigate the role of elevated Phospholipase D (PLD) expression in suppressing DNA damage-induced apoptosis.
  • To elucidate the mechanism by which PLD affects p53 stabilization and activation in response to DNA damage.

Main Methods:

  • Assessing the impact of elevated PLD expression on p53 stabilization following DNA damage.
  • Measuring MDM2 (E3 ubiquitin ligase) expression and p53 turnover rates in cells with altered PLD levels.
  • Investigating the involvement of mTOR, mitogen-activated protein kinase, and PI3K/Akt pathways using specific inhibitors.

Main Results:

  • Elevated PLD expression suppressed DNA damage-induced apoptosis and p53 stabilization.
  • PLD overexpression increased MDM2 expression, accelerating p53 degradation.
  • PLD1-induced effects on MDM2 and p53 were dependent on mTOR and MAPK pathways, with basal PI3K activity partially required for MDM2 induction.

Conclusions:

  • Survival signals generated by Phospholipase D (PLD) function, in part, by suppressing the p53 response pathway.
  • PLD influences p53 regulation through MDM2-mediated turnover, modulated by mTOR and MAPK signaling cascades.

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