RhoB protects human keratinocytes from UVB-induced apoptosis through epidermal growth factor receptor signaling
RhoB protects human keratinocytes from UVB-induced apoptosis through epidermal growth factor receptor signaling
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DOI：
10.1074/jbc.m508650200
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发表时间：
2005-12-30
影响因子：
4.8
通讯作者：
Favre, G
中科院分区：
文献类型：
--
作者：
Canguilhem, B;Pradines, A;Favre, G
皮肤暴露在UVB光下会导致DNA光斑的形成，从而导致细胞死亡、突变和致癌事件的发生。特定的蛋白质被UVB激活，然后触发导致细胞反应的信号转导途径。这些信号分子的改变被认为是UVB照射促进肿瘤的基本事件。RhoB编码一个小的GTPase，已被确定为DNA损伤诱导基因。RhoB参与表皮生长因子（EGF）受体运输、细胞骨架组织、细胞转化和存活。我们分析了RhoB的调控，并阐明了其在HaCaT角质形成细胞对相关环境UVB照射的细胞反应中的作用。我们在这里报道，在暴露于UVB的5分钟内，活化的gtp结合形式的RhoB迅速增加，然后RhoB蛋白水平随着EGF受体（EGFR）的激活而增加。抑制uvb诱导的EGFR激活可阻止RhoB蛋白表达和AKT磷酸化，但不能阻止RhoB的早期激活。用特异性小干扰rna阻断uvb诱导的RhoB表达，通过抑制EGFR表达抑制AKT和糖原合成酶激酶-3 β磷酸化。此外，RhoB的下调增强了uvb诱导的细胞凋亡。相反，RhoB过表达保护角质细胞免受uvb诱导的凋亡。这些结果表明，在UVB照射下，RhoB受两个步骤的调控，包括早期egfr独立的RhoB激活，然后是egfr依赖的RhoB表达诱导。此外，我们已经证明RhoB在UVB暴露后调节角质形成细胞的存活中是必不可少的，这表明它在光致癌中可能起作用。
Exposure of the skin to UVB light results in the formation of DNA photolesions that can give rise to cell death, mutations, and the onset of carcinogenic events. Specific proteins are activated by UVB and then trigger signal transduction pathways that lead to cellular responses. An alteration of these signaling molecules is thought to be a fundamental event in tumor promotion by UVB irradiation. RhoB, encoding a small GTPase has been identified as a DNA damage-inducible gene. RhoB is involved in epidermal growth factor (EGF) receptor trafficking, cytoskeletal organization, cell transformation, and survival. We have analyzed the regulation of RhoB and elucidated its role in the cellular response of HaCaT keratinocytes to relevant environmental UVB irradiation. We report here that the activated GTP-bound form of RhoB is increased rapidly within 5 min of exposure to UVB, and then RhoB protein levels increased concomitantly with EGF receptor ( EGFR) activation. Inhibition of UVB-induced EGFR activation prevents RhoB protein expression and AKT phosphorylation but not the early activation of RhoB. Blocking UVB-induced RhoB expression with specific small interfering RNAs inhibits AKT and glycogen synthase kinase-3 beta phosphorylation through inhibition of EGFR expression. Moreover, down-regulation of RhoB potentiates UVB-induced cell apoptosis. In contrast, RhoB overexpression protects keratinocytes against UVB-induced apoptosis. These results indicated that RhoB is regulated upon UVB exposure by a two-step process consisting of an early EGFR-independent RhoB activation followed by an EGFR-dependent induction of RhoB expression. Moreover, we have demonstrated that RhoB is essential in regulating keratinocyte cell survival after UVB exposure, suggesting its potential role in photocarcinogenesis.