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.

journal_name

Mol Cell

journal_title

Molecular cell

authors

Oliver TG,Meylan E,Chang GP,Xue W,Burke JR,Humpton TJ,Hubbard D,Bhutkar A,Jacks T

doi

10.1016/j.molcel.2011.06.012

subject

Has Abstract

pub_date

2011-07-08 00:00:00

pages

57-71

issue

1

eissn

1097-2765

issn

1097-4164

pii

S1097-2765(11)00453-9

journal_volume

43

pub_type

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