Abstract 4007: Cooperative regulation of Stat3 signaling by TC-PTP, SHP1, and SHP2 in keratinocytes following UVB irradiation

Abstract

Abstract Stat3 is initially dephosphorylated in murine keratinocytes in response to UVB irradiation. Treatment with Na3VO4 desensitized keratinocytes to UVB-induced apoptosis with the recovery of phosphorylated Stat3 protein levels, implying that a protein tyrosine phosphatase (PTP) is involved in this mechanism. In the current work, we report that three PTPs including TC45, the nuclear form of TC-PTP, SHP1, and SHP2 are involved in this rapid dephosphorylation of Stat3 in keratinocytes induced by UVB irradiation. Dephosphorylation of Stat3 was increased rapidly after UVB irradiation of cultured keratinocytes. Knockdown of TC-PTP, SHP1, or SHP2 using RNAi showed that these PTPs are in part responsible for Stat3 dephosphorylation following UVB irradiation. The level of phosphorylated Stat3 was significantly higher in keratinocytes transfected with TC-PTP, SHP1, or SHP2 siRNA in the presence or absence of UVB compared with keratinocytes transfected with control siRNA. TC45, the isoform of TC-PTP expressed in keratinocytes, was mainly localized in the cytoplasm of keratinocytes and translocated from cytoplasm to nucleus upon UVB irradiation. Stat3 dephosphorylation was associated with nuclear translocation of TC45. Further studies revealed that simultaneous knockdown of all three phosphatases, TC45, SHP1, and SHP2, using RNAi recovered the level of phosphorylated Stat3 upon UVB irradiation. In mouse epidermis, the level of phosphorylated Stat3 also was initially decreased by UVB irradiation followed by a significant increase at later time points after UVB exposure. The expression patterns of Stat3 target genes, such as cyclin D1 and c-Myc, followed the changes in activated Stat3 in response to UVB irradiation. Collectively, these results suggest that three phosphatases, TC45, SHP1, and SHP2, are responsible for UVB-mediated Stat3 dephosphorylation and may serve as part of an initial protective mechanism against UV skin carcinogenesis. Supported by NIH grants CA105345, CA76520 and an Odyssey Fellowship to DJK. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4007.