Caspase-2-Mediated Cleavage of Mdm2 Creates a p53-Induced Positive Feedback Loop
Author(s)Oliver, Trudy; Meylan, Etienne; Chang, Gregory P.; Xue, Wen; Burke, James R.; Humpton, Timothy J.; Hubbard, Diana D.; Bhutkar, Arjun (AJ); Jacks, Tyler E.; ... Show more Show less
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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.
DepartmentDavid H. Koch Institute for Integrative Cancer Research at MIT
Oliver, Trudy G., Etienne Meylan, Gregory P. Chang, Wen Xue, James R. Burke, Timothy J. Humpton, Diana Hubbard, Arjun Bhutkar, and Tyler Jacks. “Caspase-2-Mediated Cleavage of Mdm2 Creates a P53-Induced Positive Feedback Loop.” Molecular Cell 43, no. 1 (July 2011): 57–71. © 2011 Elsevier Inc.
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