| First Author | Oliver TG | Year | 2011 |
| Journal | Mol Cell | Volume | 43 |
| Issue | 1 | Pages | 57-71 |
| PubMed ID | 21726810 | Mgi Jnum | J:174374 |
| Mgi Id | MGI:5085944 | Doi | 10.1016/j.molcel.2011.06.012 |
| Citation | Oliver TG, et al. (2011) Caspase-2-Mediated Cleavage of Mdm2 Creates a p53-Induced Positive Feedback Loop. Mol Cell 43(1):57-71 |
| abstractText | 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. |
