title: Activation of T-cell protein-tyrosine phosphatase suppresses keratinocyte survival and proliferation following UVB irradiation.
abstract: 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.
authors.affiliation: From the Edinburg Regional Academic Health Center, Medical Research Division, University of Texas Health Science Center at San Antonio, Edinburg, Texas 78541 and the Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229.
authors.forename: Hyunseung
authors.initials: H
authors.lastname: Lee
authors.affiliation: From the Edinburg Regional Academic Health Center, Medical Research Division, University of Texas Health Science Center at San Antonio, Edinburg, Texas 78541 and.
authors.forename: Liza D
authors.initials: LD
authors.lastname: Morales
authors.affiliation: the Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Slaga
authors.affiliation: From the Edinburg Regional Academic Health Center, Medical Research Division, University of Texas Health Science Center at San Antonio, Edinburg, Texas 78541 and the Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229 KimDJ@uthscsa.edu.
authors.forename: Dae Joon
authors.initials: DJ
authors.lastname: Kim
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects; D004789:Enzyme Activation / Q000528:radiation effects; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D015603:Keratinocytes / Q000166:cytology / Q000201:enzymology / Q000528:radiation effects*; D051379:Mice; D010766:Phosphorylation; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000172:deficiency / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014466:Ultraviolet Rays
chemical_list: D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; C516653:Ptpn2 protein, mouse; D053148:Caspase 3
keywords: Cell Proliferation; Keratinocyte; STAT3; Skin; Tyrosine-protein Phosphatase (Tyrosine Phosphatase); UVB