Smad4 loss in mouse keratinocytes leads to increased susceptibility to UV carcinogenesis with reduced Ercc1-mediated DNA repair.
Smad4 loss in mouse keratinocytes leads to increased susceptibility to UV carcinogenesis with reduced Ercc1-mediated DNA repair.
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DOI：
10.1038/jid.2013.213
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发表时间：
2013-11
影响因子：
6.5
通讯作者：
Wang, Xiao-Jing
中科院分区：
文献类型：
--
作者：
Mitra, Doyel;Fernandez, Pamela;Bian, Li;Song, Ningjing;Li, Fulun;Han, Gangwen;Wang, Xiao-Jing
Smad4丢失在人类皮肤鳞状细胞癌（SCC）中经常发生，但尚不清楚这种丢失是否会增加紫外线诱导（UV）的致癌作用，这是皮肤癌的主要病因。在本研究中，角化细胞特异性Smad4缺失（K14.Smad4−/−）的小鼠和野生型（WT）幼崽被长期紫外线照射。与WT相比，K14。Smad4−/−小鼠表现出更高的DNA损伤和对紫外线诱导的皮肤癌的易感性。在参与修复紫外线诱导的DNA损伤的基因中，在紫外线处理的K14中，切除修复交叉互补组1 (Ercc1) mRNA显著降低。Smad4−/−皮肤与WT皮肤的比较。进一步分析表明，Smad4缺失导致Snail与Ercc1调控元件的结合减少，从而导致Ercc1转录减少。一致地，将Snai1瞬时转染到Smad4 - / -角质形成细胞会增加紫外线诱导的DNA损伤的修复。将Ercc1转染到Smad4 - / -角化细胞中，可恢复紫外线诱导的DNA损伤的修复。此外，免疫染色显示Smad4蛋白的存在与人皮肤SCC和癌前光化性角化病（AK）中Snail和Ercc1蛋白的存在相关。总的来说，Smad4缺失相关的蜗牛减少损害了ercc1介导的DNA修复，增加了紫外线诱导的皮肤癌发生。因此，我们确定了蜗牛在紫外线诱导的DNA修复中的作用。
Smad4 loss occurs frequently in human skin squamous cell carcinoma (SCC), but it is unknown if this loss increases ultraviolet-induced (UV) carcinogenesis, a major etiological factor in skin cancer. In the present study, mice with keratinocyte-specific Smad4 deletion (K14.Smad4−/−) and wildtype (WT) littermates were chronically UV-irradiated. Compared to WT, K14.Smad4−/− mice exhibited increased DNA damage and increased susceptibility to UV-induced skin cancer. Among genes involved in repairing UV-induced DNA damage, Excision repair cross-complementation group1 (Ercc1) mRNA was significantly reduced in UV treated K14.Smad4−/− skin compared to WT skin. Further analysis revealed that Smad4 loss confers reduced Snail binding to the Ercc1 regulatory elements, resulting in reduced Ercc1 transcription. Consistently, transient transfection of Snai1 into Smad4−/− keratinocytes led to increased repair of UV-induced DNA lesions. Transfection of Ercc1 into Smad4−/− keratinocytes restored repair of UV-induced DNA damage. Further, immunostaining revealed that the presence of Smad4 protein is associated with the presence of Snail and Ercc1 proteins in human skin SCC and precancerous actinic keratoses (AK). Collectively, Smad4 loss associated Snail reduction compromises Ercc1-mediated DNA repair, contributing to increased UV-induced skin carcinogenesis. Thus we identified a role for Snail in UV-induced DNA repair.
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影响因子：
7.8
作者：
Martini, E;Roche, D M;Marheineke, K;Verreault, A;Almouzni, G
通讯作者：
Almouzni, G
影响因子：
2.9
作者：
Kawashima, Atsunari;Takayama, Hitoshi;Tsujimura, Akira
通讯作者：
Tsujimura, Akira
DOI：
10.1073/pnas.0603779103
发表时间：
2006-06-27
影响因子：
11.1
作者：
Marti, Thomas M.;Hefner, Eli;Cleaver, James E.
通讯作者：
Cleaver, James E.
影响因子：
21.3
作者：
Batlle, E;Sancho, E;de Herreros, AG
通讯作者：
de Herreros, AG
影响因子：
5.3
作者：
Kajita, M;McClinic, KN;Wade, PA
通讯作者：
Wade, PA