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

Molecular cell | Jul 8, 2011

http://www.ncbi.nlm.nih.gov/pubmed/21726810

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 RIS Download

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

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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:

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