Analysis of the role of Stat3 in protecting apoptosis in skin

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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.