Caspase-2-mediated cleavage of Mdm2 creates a p53-induced positive feedback loop

Mol Cell. 2011 Jul 8;43(1):57-71. doi: 10.1016/j.molcel.2011.06.012.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / metabolism
  • Carrier Proteins / physiology
  • Caspase 2 / metabolism
  • Caspase 2 / physiology*
  • Cisplatin / pharmacology
  • Cysteine Endopeptidases / metabolism
  • Cysteine Endopeptidases / physiology*
  • DNA Damage
  • Death Domain Receptor Signaling Adaptor Proteins
  • Feedback, Physiological
  • Humans
  • Proto-Oncogene Proteins c-mdm2 / metabolism*
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Carrier Proteins
  • Death Domain Receptor Signaling Adaptor Proteins
  • PIDD1 protein, human
  • Tumor Suppressor Protein p53
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • CASP2 protein, human
  • Caspase 2
  • Cysteine Endopeptidases
  • Cisplatin