NF-κB/Egr-1/Gadd45 are sequentially activated upon UVB irradiation to mediate epidermal cell death
NF-κB/Egr-1/Gadd45 are sequentially activated upon UVB irradiation to mediate epidermal cell death
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DOI：
10.1038/sj.emboj.7600501
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发表时间：
2005-01-12
期刊：
影响因子：
11.4
通讯作者：
Virolle, T
中科院分区：
文献类型：
--
作者：
Thyss, R;Virolle, V;Virolle, T
长期暴露在阳光下会导致严重的皮肤疾病，如致癌。由紫外线B（UVB）照射引发的细胞死亡过程至关重要，因为它保护周围组织免受具有转化风险的细胞的出现和积累。在这里，我们表明，抑制NF-κ B和Egr- 1的表达大大抑制UVB介导的细胞死亡。此外，我们证明，Egr- 1诱导UVB照射后，通过NF-κ B活化和结合的Egr- 1启动子内的p65/ RelA。我们表明，Egr- 1有助于Gadd 45 a和Gadd 45 b基因，这是参与细胞周期，DNA修复和凋亡的控制，通过直接结合到他们的启动子的调节。我们的研究首次证明了涉及NF-κ B、Egr- 1和Gadd 45顺序激活的信号级联反应诱导UVB介导的细胞死亡。在这个途径的每一个主角的诱导失败改变UVB介导的细胞死亡过程。因此，损伤的级联反应可能是在发病的皮肤癌介导的遗传毒性应激。
Chronic sun exposure can lead to severe skin disorders such as carcinogenesis. The cell death process triggered by ultraviolet B ( UVB) irradiation is crucial because it protects the surrounding tissue from the emergence and the accumulation of cells that bear the risk of becoming transformed. Here, we show that repression of NF-kappaB and Egr- 1 expression drastically inhibits UVB- mediated cell death. Furthermore, we demonstrate that Egr- 1 is induced upon UVB irradiation through NF-kappaB activation and the binding of p65/ RelA within the Egr- 1 promoter. We show that Egr- 1 contributes to the regulation of the Gadd45a and Gadd45b genes, which are involved in the control of cell cycle, DNA repair and apoptosis, by direct binding to their promoter. Our study demonstrates for the first time a signaling cascade involving sequential activation of NF-kappaB, Egr- 1 and Gadd45 to induce UVB- mediated cell death. Failure in the induction of each protagonist of this pathway alters the UVB- mediated cell death process. Therefore, impairment of the cascade could be at the onset of skin carcinogenesis mediated by genotoxic stress.