The death domain kinase RIP has an essential role in DNA damage-induced NF-κB activation

• DOI: 10.1101/gad.1062403
• Publication Date: 2003-04-01T21:44:19Z
• Authors: Gang Min Hur; Joseph Lewis; Qingfeng Yang; Yong Lin; Hiroyasu Nakano; Sergei Nedospasov; Zheng-gang Liu
• Keywords: Mice, Knockout; TNF Receptor-Associated Factor 5; 0303 health sciences; Transcription, Genetic; Tumor Suppressor Proteins; NF-kappa B; Proteins; Cell Cycle Proteins; Ataxia Telangiectasia Mutated Proteins; Fibroblasts; Protein Serine-Threonine Kinases; TNF Receptor-Associated Factor 2; Receptors, Tumor Necrosis Factor; DNA-Binding Proteins; Mice; 03 medical and health sciences; Receptor-Interacting Protein Serine-Threonine Kinases; Animals; DNA Damage

The transcription factor NF-κB is activated when cells are exposed to genotoxic stress. It has been suggested that DNA damage will trigger a cytoplasmic signaling that leads to the activation of IKK and NF-κB, but the signaling components upstream of IKK have not yet been identified. Here we report that the receptor interacting protein, RIP, is the IKK upstream component, essential for the activation of NF-κB by DNA damage. Also, our findings suggest that this NF-κB activation by DNA damage is not mediated by autocrine or TNF-R1 signaling pathway. In wild-type fibroblasts, DNA damage induced by agents such as adriamycin, campthothecin, and ionizing radiation induces NF-κB activation. We found, however, that DNA damage failed to activate NF-κB in RIP−/− fibroblasts. The induction of IκBα degradation by DNA damage was normal in TNF-R1−/−, TRAF2−/−, TRAF5−/− and FADD−/− fibroblasts or when de novo protein synthesis was blocked. More importantly, the reconstitution of RIP expression in RIP−/− cells restores DNA damage-induced NF-κB activation. We also found that RIP forms a complex with IKK in response to DNA damage. Therefore, our study provides a possible mechanism for the initiation of the cytoplasmic signaling to activate NF-κB in response to DNA damage.