Mlacki Michal, Darido Charbel, Jane Stephen M, Wilanowski Tomasz
Laboratory of Signal Transduction, Nencki Institute of Experimental Biology, Warsaw, Poland.
Department of Medicine, Monash University Central Clinical School, Prahran, Victoria, Australia.
PLoS One. 2014 Feb 20;9(2):e89247. doi: 10.1371/journal.pone.0089247. eCollection 2014.
The Grainyhead-like 1 (GRHL1) transcription factor regulates the expression of desmosomal cadherin desmoglein 1 (Dsg1) in suprabasal layers of the epidermis. As a consequence, the epidermis of Grhl1-null mice displays fewer desmosomes that are abnormal in structure. These mice also exhibit mild chronic skin barrier defects as evidenced by altered keratinocyte terminal differentiation, increased expression of inflammatory markers and infiltration of the skin by immune cells. Exposure of Grhl1 (-/-) mice to a standard chemical skin carcinogenesis protocol results in development of fewer papillomas than in wild type control animals, but with a rate of conversion to squamous cell carcinoma (SCC) that is strikingly higher than in normal littermates. The underlying molecular mechanism differs from mice with conditional ablation of a closely related Grhl family member, Grhl3, in the skin, which develop SCC due to the loss of expression of phosphatase and tensin homolog (PTEN) and activation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR) signaling pathway.
颗粒头样蛋白1（GRHL1）转录因子调节表皮基底层上方各层中桥粒钙黏蛋白桥粒芯糖蛋白1（Dsg1）的表达。因此，GRHL1基因敲除小鼠的表皮中桥粒数量减少且结构异常。这些小鼠还表现出轻度慢性皮肤屏障缺陷，表现为角质形成细胞终末分化改变、炎症标志物表达增加以及免疫细胞浸润皮肤。将GRHL1（-/-）小鼠暴露于标准化学皮肤致癌方案下，其乳头状瘤的发生数量比野生型对照动物少，但转化为鳞状细胞癌（SCC）的比率明显高于正常同窝小鼠。其潜在分子机制与皮肤中条件性敲除密切相关的GRHL家族成员GRHL3的小鼠不同，后者因磷酸酶和张力蛋白同源物（PTEN）表达缺失以及磷脂酰肌醇3激酶（PI3K）/蛋白激酶B（AKT）/雷帕霉素靶蛋白（mTOR）信号通路激活而发生SCC。
