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Signal Transducer and Activator of Transcription 3 Is a Key Regulator of Keratinocyte Survival and Proliferation following UV Irradiation

Departments of ¹ Dermatology and ² Social and Environmental Medicine, Osaka University Graduate School of Medicine; ³ Graduate School of Frontier Biosciences, Osaka University; ⁴ Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Suita, Osaka, Japan; ⁵ Department of Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas; ⁶ Cellular Physiology Laboratory, RIKEN, The Institute of Physical and Chemical Research, Wako, Saitama, Japan; and ⁷ Radioisotope Research Center, Nara Medical University, Kashihara, Japan

Requests for reprints: John DiGiovanni, Department of Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, P.O. Box 389, Smithville, TX 78957. Phone: 512-237-9414; Fax: 512-237-2444; E-mail: jdigiovanni{at}sprd1.mdacc.tmc.edu.

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 down-regulation 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.

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