Abstract 2537: UVB irradiation induces nuclear translocation of TC-PTP in keratinocytes

Abstract

Abstract Ultraviolet B radiation (UVB) can cause DNA damage, induce gene mutations and modulate intracellular signal transduction contributing to the development of skin cancer. Signal transducer and activator of transcription 3 (Stat3) modulates various physiological functions, including apoptosis, cell cycle regulation, and tumor angiogenesis through regulation of gene expression, and its constitutive activation is associated with human epithelial cancers. Recent studies demonstrated that T-cell protein tyrosine phosphatase (TC-PTP) dephosphorylates activated Stat3 in keratinocytes after UVB irradiation. In the current work, we report that TC-PTP translocates from the cytosol to the nucleus and dephosphorylates Stat3 following UVB irradiation in keratinocytes. Western blot analysis showed that TC-PTP mainly localized in the cytoplasm of keratinocytes and translocated from cytoplasm to nucleus upon UVB irradiation. Immunofluorescence analysis of the exogenous expression of TC-PTP confirmed its nuclear translocation, and showed that nuclear translocation of TC-PTP occurs independently of its phosphatase activity. Nuclear translocation of TC-PTP was increased with increased dose of UVB exposure. Dephosphorylation of Stat3 by TC-PTP was enhanced after UVB irradiation of cultured keratinocytes with nuclear accumulation of TC-PTP. Knockdown of TC-PTP with siRNA suppressed dephoshorylation of Stat3 and enhanced cell viability in response to UVB irradiation. UVB irradiation also induced expression of 14-3-3α, a protein that has been shown to be involved in the transport of proteins. Further studies revealed that UVB-induced nuclear translocation of TC-PTP was effectively inhibited by knockdown of 14-3-3α, suggesting 14-3-3α is involved in nuclear import of TC-PTP. These results indicate that TC-PTP plays an important role as a regulator of Stat3 signaling in keratinocytes upon UVB irradiation. Nuclear translocation of TC-PTP is regulated by a 14-3-3α-dependent signaling pathway, resulting in the rapid dephosphorylation of activated Stat3 in the nucleus. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2537. doi:1538-7445.AM2012-2537