title: Caspase-2-mediated cleavage of Mdm2 creates a p53-induced positive feedback loop.
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.
authors: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors: Trudy G
authors: TG
authors: Oliver
authors: Etienne
authors: E
authors: Meylan
authors: Gregory P
authors: GP
authors: Chang
authors: Wen
authors: W
authors: Xue
authors: James R
authors: JR
authors: Burke
authors: Timothy J
authors: TJ
authors: Humpton
authors: Diana
authors: D
authors: Hubbard
authors: Arjun
authors: A
authors: Bhutkar
authors: Tyler
authors: T
authors: Jacks
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology; D053143:Caspase 2 / Q000378:metabolism / Q000502:physiology*; D002945:Cisplatin / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000378:metabolism / Q000502:physiology*; D004249:DNA Damage; D053418:Death Domain Receptor Signaling Adaptor Proteins; D025461:Feedback, Physiological; D006801:Humans; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D053418:Death Domain Receptor Signaling Adaptor Proteins; C485896:PIDD1 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C490360:CASP2 protein, human; D053143:Caspase 2; D003546:Cysteine Endopeptidases; D002945:Cisplatin