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 language | English |
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Pages (from-to) | 57-71 |
Number of pages | 15 |
Journal | Molecular Cell |
Volume | 43 |
Issue number | 1 |
Early online date | 7 Jul 2011 |
DOIs | |
Publication status | Published - 8 Jul 2011 |
Keywords
- caspase-2-PIDDosome
- genetoxic stress
- chemotherapy resistance
- growth arrest
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology