Sequential DNA damage-independent and -dependent activation of NF-κB by UV
Sequential DNA damage-independent and -dependent activation of NF-κB by UV
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DOI：
10.1093/emboj/17.17.5170
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发表时间：
1998-09-01
期刊：
影响因子：
11.4
通讯作者：
Herrlich, P
中科院分区：
文献类型：
--
作者：
Bender, K;Göttlicher, M;Herrlich, P
HeLa 细胞或原代人皮肤成纤维细胞的紫外线照射引起的 NF-kappa B 激活以两种重叠的动力学但完全不同的机制发生。尽管两种机制都涉及诱导 NF-κ B 从 I kappa B α 解离以及 I kappa B α 降解，但降解和信号转导的目标不同。 30 分钟至大约 6 小时的早期 I kappa B α 降解不是由紫外线诱导的 DNA 损伤引发的。它不需要 I kappa B 激酶 (IKK)，如显性失活激酶亚基的引入所示，并且不依赖于可磷酸化底物 I kappa B α（在位置 32 和 36 处携带丝氨酸）的存在。然而，诱导的 I kappa B α 降解需要完整的 N 端（位置 1-36）和 C 端（位置 277-287）序列。在紫外线照射后 15-20 小时的后期时间点，I kappa B 降解和 NF-kappa B 激活是通过 DNA 损伤诱导的 IL-1 α 前体裂解、IL-1 α 释放和 IL-1 α 的自分泌/旁分泌作用介导的。晚期诱导的 I kappa B α 需要 Ser32 和 Ser36 的存在。最新的机制表明存在从细胞核中的光产物到细胞质的信号转移。 “警报素”IL-1 α 的释放可能是阳光照射产生的一些全身效应的原因。
NF-kappa B activation in response to UV irradiation of HeLa cells or of primary human skin fibroblasts occurs with two overlapping kinetics but totally different mechanisms. Although both mechanisms involve induced dissociation of NF-kappa B from I kappa B alpha and degradation of I kappa B alpha, targeting for degradation and signaling are different. Early I kappa B alpha degradation at 30 min to similar to 6 h is not initiated by UV-induced DNA damage. It does not require I kappa B kinase (IKK), as shown by introduction of a dominant-negative kinase subunit, and does not depend on the presence of the phosphorylatable substrate, I kappa B alpha, carrying serines at positions 32 and 36. Induced I kappa B alpha degradation requires, however, intact N- (positions 1-36) and C-terminal (positions 277-287) sequences. I kappa B degradation and NF-kappa B activation at late time points, 15-20 h after UV irradiation, is mediated through DNA damage-induced cleavage of IL-1 alpha precursor, release of IL-1 alpha and autocrine/paracrine action of IL-1 alpha. Late-induced I kappa B alpha requires the presence of Ser32 and Ser36. The late mechanism indicates the existence of signal transfer from photoproducts in the nucleus to the cytoplasm. The release of the 'alarmone' IL-1 alpha may account for some of the systemic effects of sunlight exposure.