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

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.

Pubmed ID: 21726810

Authors

  • Oliver TG
  • Meylan E
  • Chang GP
  • Xue W
  • Burke JR
  • Humpton TJ
  • Hubbard D
  • Bhutkar A
  • Jacks T

Journal

Molecular cell

Publication Data

July 8, 2011

Associated Grants

  • Agency: NCI NIH HHS, Id: P30 CA014051
  • Agency: NCI NIH HHS, Id: P30 CA014051-39
  • Agency: NCI NIH HHS, Id: P30 CA014051-40
  • Agency: NCI NIH HHS, Id: P30 CA014051-41
  • Agency: NCI NIH HHS, Id: P30-CA14051
  • Agency: Howard Hughes Medical Institute, Id:
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

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