Targeted deletion of Rad9 in mouse skin keratinocytes enhances genotoxin-induced tumor development.
Targeted deletion of Rad9 in mouse skin keratinocytes enhances genotoxin-induced tumor development.
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DOI：
10.1158/0008-5472.can-07-5670
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发表时间：
2008-07-15
期刊：
影响因子：
11.2
通讯作者：
Hang H
中科院分区：
文献类型：
--
作者：
Hu Z;Liu Y;Zhang C;Zhao Y;He W;Han L;Yang L;Hopkins KM;Yang X;Lieberman HB;Hang H
Rad9基因从酵母到人类在进化上是保守的，在基因组维持、DNA修复和细胞周期检查点控制中发挥着关键作用。然而，该基因在肿瘤发生中的作用还不是很清楚。小鼠的Rad9零突变会导致胚胎死亡。在这项研究中，我们建立了只在角质形成细胞中缺失小鼠Rad9，Mrad9的小鼠，以允许检查该基因在肿瘤发展中的潜在功能。Mrad9+/−或Mrad9−/−角质形成细胞的小鼠没有明显的、自发的形态缺陷，看起来与野生型对照组相似。与Mrad9+/−/−和Mrad9+/+小鼠相比，将致癌物7，12-二甲基苯并菲涂在动物的皮肤上会导致Mrad9−小鼠更早发生肿瘤和更频繁地形成衰老皮肤斑块。损伤反应基因p21、P53和Mrad9B在Mrad9+/+−/−中的表达水平高于Mrad9+/+皮肤。从Mrad9−/−皮肤分离的角质形成细胞比Mrad9+/+角质形成细胞具有更多的自发和DMBA诱导的DNA双链断裂，且加入抗氧化剂EGCG后其水平降低。这些数据表明，Mrad9在维持基因组稳定性和防止角质形成细胞中的肿瘤发展方面发挥着重要作用。
The Rad9 gene is evolutionarily conserved from yeast to human, and plays crucial roles in genomic maintenance, DNA repair and cell cycle checkpoint controls. However, the function of this gene with respect to tumorigenesis is not well understood. A Rad9-null mutation in mice causes embryonic lethality. In this study, we created mice in which mouse Rad9, Mrad9, was deleted only in keratinocytes to permit examination of the potential function of the gene in tumor development. Mice with Mrad9+/− or Mrad9−/− keratinocytes demonstrated no overt, spontaneous morphological defects and appeared similar to wild-type controls. Painting the carcinogen 7,12-dimethylbenzanthracene (DMBA) onto the skin of the animals caused earlier onset and more frequent formation of tumors and senile skin plaques in Mrad9−/− mice, compared to Mrad9+/− and Mrad9+/+ littermates. DNA damage response genes p21, p53 and Mrad9B were expressed at higher levels in Mrad9−/− relative to Mrad9+/+ skin. Keratinocytes isolated from Mrad9−/− skin had more spontaneous and DMBA-induced DNA double strand breaks than Mrad9+/+ keratinocytes, and the levels were reduced by incubation with the antioxidant EGCG. These data suggest that Mrad9 plays an important role in maintaining genomic stability and preventing tumor development in keratinocytes.