Activation of T-cell Protein-tyrosine Phosphatase Suppresses Keratinocyte Survival and Proliferation following UVB Irradiation

作者：Lee Hyunseung; Morales Liza D; Slaga Thomas J; Kim Dae Joon^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2015, 290(1): 13-24.

DOI：10.1074/jbc.M114.611681

• Cell Proliferation
• Keratinocyte
• Skin
• STAT3
• Tyrosine-protein Phosphatase (Tyrosine Phosphatase)
• UVB

Background: STAT3 promotes UVB-induced keratinocyte cell proliferation. Results: TC-PTP inhibits STAT3-mediated mouse keratinocyte skin cell proliferation and survival following UVB irradiation. Conclusion: TC-PTP plays an important role in the skin cell response to UVB radiation by regulating cell proliferation and survival. Significance: TC-PTP shows tumor-suppressive capabilities in skin.
Chronic exposure to UV radiation can contribute to the development of skin cancer by promoting protein-tyrosine kinase (PTK) signaling. Studies show that exposure to UV radiation increases the ligand-independent activation of PTKs and induces protein-tyrosine phosphatase (PTP) inactivation. In the present work, we report that T-cell PTP (TC-PTP) activity is stimulated during the initial response to UVB irradiation, which leads to suppression of keratinocyte cell survival and proliferation via the down-regulation of STAT3 signaling. Our results show that TC-PTP-deficient keratinocyte cell lines expressed a significantly increased level of phosphorylated STAT3 after exposure to low dose UVB. This increase corresponded with increased cell proliferation in TC-PTP-deficient keratinocytes following UVB irradiation. Loss of TC-PTP also reduced UVB-induced apoptosis. Corroborating with these results, overexpression of TC-PTP in keratinocyte cell lines yielded a decrease in phosphorylated STAT3 levels, which corresponded with a significant decrease in cell proliferation in response to low dose UVB. We demonstrate that TC-PTP activity was increased upon UVB exposure, and overexpression of TC-PTP in keratinocyte cell lines further increased its activity in the presence of UVB. Treatment of TC-PTP-deficient keratinocytes with the STAT3 inhibitor STA21 significantly reduced cell viability following UVB exposure in comparison with untreated TC-PTP-deficient keratinocytes, confirming that the effect of TC-PTP on cell viability is mediated by STAT3 dephosphorylation. Combined, our results indicate that UVB-mediated activation of TC-PTP plays an important role in the STAT3-dependent regulation of keratinocyte cell proliferation and survival. Furthermore, these results suggest that TC-PTP may be a novel potential target for the prevention of UVB-induced skin cancer.

• 出版日期2015-1-2