PTEN is a negative regulator of STAT3 activation in human papillomavirus-infected cells.
Laryngeal papillomas are caused by infection of the laryngeal epithelium by human papillomavirus type 6 or type 11 (HPV-6/-11). Previous studies in our laboratory have demonstrated an increase in PI3 kinase levels in papilloma tissue. However, activation of the downstream effector of PI3 kinase, protein kinase B (PKB/Akt), was reduced. This observation was explained by the elevated expression of the phosphatase and tensin homologue (PTEN), a recently characterized tumour suppressor, in papilloma tissue. Recent investigation of the possible functional roles of PTEN during papilloma development has now indicated that the level of tyrosine(705)-phosphorylated signal transducer and activator of transcription 3 [PTyr(705)STAT3] could be inversely correlated to that of PTEN as well. In vitro phosphatase assays suggested the presence of an increased level of a PTyr(705)STAT3 phosphatase in papilloma extract. Immunodepletion of PTEN from papilloma extracts resulted in a reduction of the PTyr(705)STAT3 phosphatase activity. Transfection of PTEN cDNA into HeLa cells attenuated STAT3 phosphorylation at Tyr(705) in a dose-dependent manner. This attenuation of STAT3 phosphorylation was independent of the STAT3 kinase. Interestingly, introduction of a lipid phosphatase mutant of PTEN (G129E) resulted in heightened PTyr(705)STAT3 phosphatase activity, relative to that obtained from wild-type PTEN transfection. These data indicate that PTEN negatively regulates STAT3 activation in HPV-infected papilloma cells. Induction of PTEN and reduction of activated STAT3 might be a result of a host defence mechanism or a virus-directed strategy to alter normal epithelial differentiation programming.
Sun
Shishinn
S
North Shore - Long Island Jewish Research Institute and Department of Otolaryngology and Communicative Disorders, Long Island Jewish Medical Center, 270-05 76th Avenue, New Hyde Park, New York 11040, USA1.
Steinberg
Bettie M
BM
North Shore - Long Island Jewish Research Institute and Department of Otolaryngology and Communicative Disorders, Long Island Jewish Medical Center, 270-05 76th Avenue, New Hyde Park, New York 11040, USA1.
D002457:Cell Extracts / Q000494:pharmacology; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins / Q000032:analysis / Q000378:metabolism*; D015536:Down-Regulation; D004848:Epithelium / Q000821:virology; D016147:Genes, Tumor Suppressor; D006367:HeLa Cells; D006801:Humans; D007822:Laryngeal Neoplasms; D007830:Larynx; D009154:Mutation; D051059:PTEN Phosphohydrolase; D010212:Papilloma; D027383:Papillomaviridae / Q000502:physiology*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D010770:Phosphotransferases / Q000378:metabolism; D019000:Phosphotyrosine; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000032:analysis / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*
D002457:Cell Extracts; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D019000:Phosphotyrosine; D010770:Phosphotransferases; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human