Li N, Karin M
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0636, USA.
Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):13012-7. doi: 10.1073/pnas.95.22.13012.
We examined the mechanisms by which two different types of photonic radiation, short wavelength UV (UV-C) and gamma radiation, activate transcription factor NF-kappaB. Exposure of mammalian cells to either form of radiation resulted in induction with similar kinetics of NF-kappaB DNA binding activity, nuclear translocation of its p65(RelA) subunit, and degradation of the major NF-kappaB inhibitor IkappaBalpha. In both cases, induction of NF-kappaB activity was attenuated by proteasome inhibitors and a mutation in ubiquitin-activating enzyme, suggesting that both UV-C and gamma radiation induce degradation of IkappaBs by means of the ubiquitin/proteasome pathway. However, although the induction of IkappaBalpha degradation by gamma rays was dependent on its phosphorylation at Ser-32 and Ser-36, UV-C-induced IkappaBalpha degradation was not dependent on phosphorylation of these residues. Even the "super repressor" IkappaBalpha mutant, which contains alanines at positions 32 and 36, was still susceptible to UV-C-induced degradation. Correspondingly, we found that gamma radiation led to activation of IKK, the protein kinase that phosphorylates IkappaBalpha at Ser-32 and Ser-36, whereas UV-C radiation did not. Furthermore, expression of a catalytically inactive IKKbeta mutant prevented NF-kappaB activation by gamma radiation, but not by UV-C. These results indicate that gamma radiation and UV-C activate NF-kappaB through two distinct mechanisms.
我们研究了两种不同类型的光子辐射，即短波紫外线（UV-C）和γ辐射，激活转录因子NF-κB的机制。将哺乳动物细胞暴露于任何一种辐射形式下，都会导致NF-κB DNA结合活性、其p65（RelA）亚基的核转位以及主要NF-κB抑制剂IκBα的降解呈现相似的动力学诱导。在这两种情况下，蛋白酶体抑制剂和泛素激活酶的突变都会减弱NF-κB活性的诱导，这表明UV-C和γ辐射均通过泛素/蛋白酶体途径诱导IκB的降解。然而，尽管γ射线诱导的IκBα降解依赖于其在Ser-32和Ser-36处的磷酸化，但UV-C诱导的IκBα降解并不依赖于这些残基的磷酸化。即使是在32位和36位含有丙氨酸的“超级抑制因子”IκBα突变体，仍然对UV-C诱导的降解敏感。相应地，我们发现γ辐射导致IKK激活，IKK是一种在Ser-32和Ser-36处使IκBα磷酸化的蛋白激酶，而UV-C辐射则不会。此外，催化无活性的IKKβ突变体的表达可阻止γ辐射激活NF-κB，但不能阻止UV-C激活NF-κB。这些结果表明，γ辐射和UV-C通过两种不同的机制激活NF-κB。
