Affiliation:
1. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, U.S.A.
Abstract
In response to UV irradiation, mammalian cells elicit a gene expression programme designed to repair damage and control cell proliferation and apoptosis. Important members of this stress response include the NF-κB (nuclear factor-κB) family. However, the mechanisms by which UV irradiation activates NF-κB are not well understood. In eukaryotes, a variety of environmental stresses are recognized and remediated by a family of protein kinases that phosphorylate the α subunit of eIF2 (eukaryotic initiation factor-2). In the present study we show that NF-κB in MEF (murine embryo fibroblast) cells is activated by UV-C and UV-B irradiation through a mechanism requiring eIF2α phosphorylation. The primary eIF2α kinase in response to UV is GCN2 (general control non-derepressible-2), with PEK/PERK (pancreatic eIF2α kinase/RNA-dependent-protein-kinase-like endoplasmic-reticulum kinase) carrying out a secondary function. Our studies indicate that lowered protein synthesis accompanying eIF2α phosphorylation, combined with eIF2α kinase-independent turnover of IκBα (inhibitor of κBα), reduces the levels of IκBα in response to UV irradiation. Release of NF-κB from the inhibitory IκBα would facilitate NF-κB entry into the nucleus and targeted transcriptional control. We also find that loss of GCN2 in MEF cells significantly enhances apoptosis in response to UV exposure similar to that measured in cells deleted for the RelA/p65 subunit of NF-κB. These results demonstrate that GCN2 is central to recognition of UV stress, and that eIF2α phosphorylation provides resistance to apoptosis in response to this environmental insult.
Subject
Cell Biology,Molecular Biology,Biochemistry
Reference54 articles.
1. UV-induced signal transduction;Bender;J. Photochem. Photobiol. B Biol.,1997
2. MAPK pathways in radiation responses;Dent;Oncogene,2003
3. Nuclear and non-nuclear targets of genotoxic agents in the induction of gene expression. Shared principles in yeast, rodents, man and plants;Herrlich;Biol. Chem.,1997
4. Activation of p53 tumor suppressor protein;Vousden;Biochim. Biophys. Acta,2002
5. NF-κB activation by ultraviolet light not dependent on a nuclear signal;Devary;Science,1993
Cited by
142 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献