Caspase-2-Mediated Cleavage of Mdm2 Creates a p53-Induced Positive Feedback Loop

Trudy G. Oliver, Etienne Meylan, Gregory P. Chang, Wen Xue, James R. Burke, Timothy J. Humpton, Diana Hubbard, Arjun Bhutkar, Tyler Jacks*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

120 Citations (Scopus)

Abstract

Caspase-2 is an evolutionarily conserved caspase, yet its biological function and cleavage targets are poorly understood. Caspase-2 is activated by the p53 target gene product PIDD (also known as LRDD) in a complex called the Caspase-2-PIDDosome. We show that PIDD expression promotes growth arrest and chemotherapy resistance by a mechanism that depends on Caspase-2 and wild-type p53. PIDD-induced Caspase-2 directly cleaves the E3 ubiquitin ligase Mdm2 at Asp 367, leading to loss of the C-terminal RING domain responsible for p53 ubiquitination. As a consequence, N-terminally truncated Mdm2 binds p53 and promotes its stability. Upon DNA damage, p53 induction of the Caspase-2-PIDDosome creates a positive feedback loop that inhibits Mdm2 and reinforces p53 stability and activity, contributing to cell survival and drug resistance. These data establish Mdm2 as a cleavage target of Caspase-2 and provide insight into a mechanism of Mdm2 inhibition that impacts p53 dynamics upon genotoxic stress.

Original languageEnglish
Pages (from-to)57-71
Number of pages15
JournalMolecular Cell
Volume43
Issue number1
Early online date7 Jul 2011
DOIs
Publication statusPublished - 8 Jul 2011

Keywords

  • caspase-2-PIDDosome
  • genetoxic stress
  • chemotherapy resistance
  • growth arrest

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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