UVB irradiation of signal transducer and activator of transcription 3 (Stat3)-deficient keratinocytes resulted in a high incidence of apoptosis compared with controls. Conversely, forced expression of Stat3 desensitized keratinocytes to UVB-induced apoptosis. Upon UVB exposure, keratinocyte Stat3 was rapidly dephosphorylated, followed by decreases of both Stat3 mRNA and protein levels in a p53-independent manner. Vanadate treatment reversed the UVB-induced downregulation of Stat3 and generation of apoptotic keratinocytes, suggesting the involvement of a tyrosine phosphatase. Furthermore, Stat3 was required for UVB-induced proliferation of follicular keratinocytes, leading to epidermal thickening. Finally, constitutive activation of Stat3 was observed in UVB-induced squamous cell carcinomas of either mice or human origin. These data suggest that Stat3 is required for survival and proliferation of keratinocytes following UVB exposure and that Stat3 is tightly regulated as part of a novel protective mechanism against UVB-induced skin cancer. (Cancer Res 2005; 65(13): 5720-9)

The hair follicle is an epidermal derivative that undergoes cycles of growth, involution, and rest. The hair cycle has well-orchestrated kinetics regulated by interactions between mesenchymal and epithelial cells, although the intracellular signals remain unclear. We previously established keratinocyte-specific Stat3-disrupted mice, by which we demonstrated that signal transducer and activator of transcription 3 (Stat3) is required for wound healing and anagen progression in the hair cycle. Growth factor-dependent migration of Stat3-disrupted keratinocytes was severely impaired, suggesting that not only wound healing but also telogen-to-anagen progression required organized keratinocyte migration in response to mesenchymal stimuli. In the present study, to examine whether Stat3 activation in keratinocytes is a prerequisite for hair cycle progression, we applied methods for experimental anagen induction to Stat3-disrupted mice. It was demonstrated that anagen was successfully induced in Stat3-disrupted as well as wild-type mice by chemical or mechanical stimulation, i.e., by topical application of phorbol 12-myristate 13-acetate (PMA) or by hair plucking, respectively. This result indicated that anagen in these methods occurred in the absence of Stat3. Furthermore, PMA stimulated the migration of Stat3-disrupted keratinocytes in vitro , supporting a hypothesis that the protein kinase C (PKC) and Stat3 pathways occur independently in the postnatal anagen induction. Both Stat3-dependent and -independent migration of keratinocytes was inhibited by a phosphoinositide 3-kinase (PI3K) inhibitor, wortmannin. Therefore, we infer that entry into anagen is mediated by at least two distinct signaling pathways: Stat3-dependent pathway for spontaneous hair cycling and Stat3-independent (probably PKC-dependent) pathway for exogenously induced hair cycling, whereas both pathways require PI3K activation.

We previously reported that STAT3 plays a crucial role in transducing a signal for migration of keratinocytes (Sano, S., Itami, S., Takeda, K., Tarutani, M., Yamaguchi, Y., Miura, H., Yoshikawa, K., Akira, S., and Takeda, J. (1999) EMBO J. 18, 4657-4668). To clarify the role of STAT3 in signaling the migration, we studied the intracellular signaling pathway through an integrin receptor in STAT3-deficient keratinocytes. STAT3-deficient keratinocytes demonstrated increased adhesiveness and fast spreading on a collagen matrix. Staining with anti-phosphotyrosine antibody revealed that STAT3-deficient keratinocytes had an increased number of tyrosyl-hyperphosphorylated focal adhesions. Analyses with immunoprecipitation revealed that p130 cas was constitutively hyperphosphorylated on tyrosine residues, while other focal adhesion molecules such as focal adhesion kinase and paxillin were not. Transfection of STAT3-deficient keratinocytes with an adenoviral vector encoding the wild-type Stat3 gene reversed not only impaired migration but also the increased tyrosine phosphorylation of p130 cas . These results strongly suggest that STAT3 in keratinocytes plays a critical role in turnover of tyrosine phosphorylation of p130 cas , modulating cell adhesiveness to the substratum leading to growth factor-dependent cell migration.Signal transducers and activators of transcription (STATs) 1 are a family of latent cytoplasmic transcription factors that are activated by many cytokines and growth factors (1-3). STATs are phosphorylated on tyrosine residues by activated kinases in receptor complexes, leading to formation of homo-or heterodimers and translocation to the nucleus in which they regulate transcription. STAT3 is activated by a variety of cytokines and growth factors such as interleukin-6, epidermal growth factor (EGF), hepatocyte growth factor (HGF), plateletderived growth factor, and granulocyte colony-stimulating factor. These cytokines and growth factors regulate the biological activities of keratinocytes (4, 5), suggesting that STAT3 plays a crucial role in keratinocytes. Because germ line STAT3 deletion leads to embryonic lethality (6), to elucidate the biological roles of STAT3 in the skin, we previously generated keratinocytespecific STAT3-deficient mice by conditional gene targeting using the Cre-loxP strategy (7). The Stat3 gene was disrupted under the control of a keratin 5 promoter. The mutant mice were born with no apparent abnormalities, and their epidermis and hair follicle development was normal at birth. However, wound healing was markedly retarded, and the second hair cycle was impaired in keratinocyte-specific Stat3 gene knockout mice. An in vitro study with cultured keratinocytes revealed that this phenotype was attributed to impaired migration because of the failure of STAT3 activation.Cell migration is composed of several concerted steps (8, 9). Migration is initiated with membrane protrusion (filopodia and leading edge) and adhesion to the extracellular matrix, followed by cell traction and the releas...

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Vitamin D was originally discovered as a factor that regulates calcium and bone metabolism. Recent advances in investigation have shown that vitamin D also functions as a regulator of cellular growth and differentiation in various tissues. The skin is not an exception from such effects of vitamin D; it is regarded as a site of its activation and action. Evidence has accumulated showing that the active form of vitamin D and its analogs suppress growth and stimulate the terminal differentiation of keratinocytes. In psoriatic lesions, epidermal keratinocytes exhibit hyper-proliferation and impaired differentiation triggered by inflammation. Therefore, it is quite reasonable that vitamin D is effective on psoriasis. Indeed, within the past decade, analogs of vitamin D3 have been used as topical therapy for psoriasis. In this review, we summarize the fundamental features of vitamin D and the development of vitamin D therapy for psoriasis. Clinical application to other skin diseases and the future of vitamin D therapy in dermatology are also discussed.