Analysis of the role of Stat3 in protecting apoptosis in skin

Stat3不仅作为细胞内信号分子，而且作为抗凋亡分子。为了阐明Stat3在表皮中的作用，我们使用Cre/loxP系统培养了角化细胞特异性Stat3敲除小鼠。突变小鼠出生时大体正常，皮肤和附属物（如毛囊）的形态发生没有改变。然而，他们表现出伤口愈合的延迟和进入第二毛发周期的失败。Stat3缺失角质形成细胞的体外细胞迁移实验显示，Stat3是生长因子依赖的细胞运动所必需的，尽管细胞增殖不受影响。我们得出结论，角化细胞的Stat3通过传递细胞迁移信号对伤口愈合和毛发循环至关重要。此外，与野生型小鼠相比，在紫外线（UV） B照射下，Stat3基因敲除小鼠产生了更多的晒伤细胞，这代表了表皮角化细胞的凋亡。提示Stat3在紫外线胁迫下具有抗细胞凋亡的作用。有报道称Stat3通过上调Bcl-xL （BCL-2家族成员）的转录水平发挥抗凋亡作用。我们使用Cre/loxP建立了角化细胞特异性bcl - xl小鼠，因为Bcl-x基因靶向生殖系导致胚胎致死，这与Stat3基因靶向一样。缺乏bcl - xl的小鼠出生时正常，皮肤和附属物没有明显变化。然而，我们发现表皮中有许多凋亡的角质形成细胞，这表明Bcl-xL是角质形成细胞存活所必需的。因为已知Stat3的激活和Bcl-xL的表达增强与许多癌症和肉瘤有关。我们现在正在研究，通过基因敲除小鼠，癌症发展和这些抗凋亡分子之间的关系。

Stat3 functions not only as an intracellular signaling molecule but as an anti-apoptotic molecule. To elucldate the role of Stat3 in the epidermis, we generated keratinocyte-speclflc Stat3 knockout mice by using the Cre/loxP system. The mutant mice were born normal in gross without alteration in the morphogenesis of skin and appendages such as hair follicles. However, they exhibited a delay in wound healing, and failure in entering of the second hair cycle. In vitro cell migration assay of Stat3-deficlent keratinocytes revealed that Stat3 is required for growth factor-dependent cell motility, although cell proliferation was not affected. We concluded that Stat3 of keratinocytes is essential for wound healing and hair cycle through transmission of signals for cell migration. Furthermore, Stat3 knockout mice generated more sunburn cells, that represent apoptotic keratinocytes in the epidermis, than wild-type mice by ultraviolet (UV) B irradiation. This result suggested that Stat3 plays an anti-apoptotic role against UV stress. It has been reported that Stat3 exert an anti-apoptotic effect through transcriptional upregulation of Bcl-xL, a member of BCL-2 family. We established keratinocyte-specific BcI-xL mice using the Cre/loxP, because Bcl-x gene targeting in the gerniline resulted in embryonic lethality so as found in Stat3 gene targeting. Bcl-xL-deficlent mice were born normal and devoid of gross change in skin and appendages. However, we found that they demonstrated many apoptotic keratinocytes in the epidermis, suggesting that Bcl-xL is required for keratinocyte survival. Since it is known that activated Stat3 and enhanced expression of Bcl-xL are associated with many cancer and sarcomas. We are now under investigation, by using knockout mice, on the relation between cancer development and these anti-apoptotic molecules.