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Cell. 2005 Dec 16;123(6):1079-92.

PIDD mediates NF-kappaB activation in response to DNA damage.

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1
Department of Biochemistry, University of Lausanne, BIL Biomedical Research Center, Chemin des Boveresses 155, CH-1066 Epalinges, Switzerland.

Abstract

Activation of NF-kappaB following genotoxic stress allows time for DNA-damage repair and ensures cell survival accounting for acquired chemoresistance, an impediment to effective cancer therapy. Despite this clinical relevance, little is known about pathways that enable genotoxic-stress-induced NF-kappaB induction. Previously, we reported a role for the p53-inducible death-domain-containing protein, PIDD, in caspase-2 activation and apoptosis in response to DNA damage. We now demonstrate that PIDD plays a critical role in DNA-damage-induced NF-kappaB activation. Upon genotoxic stress, a complex between PIDD, the kinase RIP1, and a component of the NF-kappaB-activating kinase complex, NEMO, is formed. PIDD expression enhances genotoxic-stress-induced NF-kappaB activation through augmented sumoylation and ubiquitination of NEMO. Depletion of PIDD and RIP1, but not caspase-2, abrogates DNA-damage-induced NEMO modification and NF-kappaB activation. We propose that PIDD acts as a molecular switch, controlling the balance between life and death upon DNA damage.

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PMID:
16360037
DOI:
10.1016/j.cell.2005.09.036
[Indexed for MEDLINE]
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