PIDD mediates NF-kappaB activation in response to DNA damage.
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.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Binding, Competitive, CRADD Signaling Adaptor Protein, Carrier Proteins, Caspase 2, Caspases, Cell Line, Tumor, Cell Nucleus, DNA, DNA Damage, Doxorubicin, Etoposide, Fatty Acids, Unsaturated, Hela Cells, Humans, Hypotonic Solutions, I-kappa B Kinase, I-kappa B Proteins, Jurkat Cells, Models, Biological, NF-kappa B, Nuclear Pore Complex Proteins, Phosphorylation, Protein Binding, Protein Transport, RNA, Small Interfering, RNA-Binding Proteins, Small Ubiquitin-Related Modifier Proteins, Transfection, Tumor Necrosis Factor-alpha, Ubiquitin, X-Linked Inhibitor of Apoptosis Protein, bcl-X Protein
Adaptor Proteins, Signal Transducing, Binding, Competitive, CRADD Signaling Adaptor Protein, Carrier Proteins, Caspase 2, Caspases, Cell Line, Tumor, Cell Nucleus, DNA, DNA Damage, Doxorubicin, Etoposide, Fatty Acids, Unsaturated, Hela Cells, Humans, Hypotonic Solutions, I-kappa B Kinase, I-kappa B Proteins, Jurkat Cells, Models, Biological, NF-kappa B, Nuclear Pore Complex Proteins, Phosphorylation, Protein Binding, Protein Transport, RNA, Small Interfering, RNA-Binding Proteins, Small Ubiquitin-Related Modifier Proteins, Transfection, Tumor Necrosis Factor-alpha, Ubiquitin, X-Linked Inhibitor of Apoptosis Protein, bcl-X Protein
Cell
Date: Dec. 16, 2005
PubMed ID: 16360037
View in: Pubmed Google Scholar
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