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.
journal_name
Mol Celljournal_title
Molecular cellauthors
Oliver TG,Meylan E,Chang GP,Xue W,Burke JR,Humpton TJ,Hubbard D,Bhutkar A,Jacks Tdoi
10.1016/j.molcel.2011.06.012subject
Has Abstractpub_date
2011-07-08 00:00:00pages
57-71issue
1eissn
1097-2765issn
1097-4164pii
S1097-2765(11)00453-9journal_volume
43pub_type
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