The death domain kinase RIP has an essential role in DNA damage-induced NF-kappa B activation.
The transcription factor NF-kappaB 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-kappaB, 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-kappaB by DNA damage. Also, our findings suggest that this NF-kappaB 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-kappaB activation. We found, however, that DNA damage failed to activate NF-kappaB in RIP-/- fibroblasts. The induction of IkappaBalpha 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-kappaB 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-kappaB in response to DNA damage.
Hur
Gang Min
GM
Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, National Institute of Health, Bethesda, MD 20892, USA.
Lewis
Joseph
J
Yang
Qingfeng
Q
Lin
Yong
Y
Nakano
Hiroyasu
H
Nedospasov
Sergei
S
Liu
Zheng-gang
ZG
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D004249:DNA Damage / Q000235:genetics*; D004268:DNA-Binding Proteins; D005347:Fibroblasts / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000502:physiology; D047992:TNF Receptor-Associated Factor 2; D048015:TNF Receptor-Associated Factor 5; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D016328:NF-kappa B; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; D047992:TNF Receptor-Associated Factor 2; D048015:TNF Receptor-Associated Factor 5; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse