title: Profibrogenic phenotype in caveolin-1 deficiency via differential regulation of STAT-1/3 proteins.
abstract: Fibrosis underlies the pathogenesis of several human diseases, which can lead to severe injury of vital organs. We previously demonstrated that caveolin-1 expression is reduced in experimental fibrosis and that caveolin-1 exerts antiproliferative and antifibrotic effects in lung fibrosis models. The signal transducers and activators of transcription (STAT) proteins, STAT1 and STAT3, can be activated simultaneously. STAT1 can inhibit cell growth and promote apoptosis while STAT3 inhibits apoptosis. Here, we show that caveolin-1-deficient (cav-1(-/-)) lung fibroblasts display dramatically upregulated STAT3 activation in response to platelet-derived growth factor-BB and transforming growth factor-β stimuli, whereas STAT1 activation is undetectable. Downregulation of protein tyrosine phosphatase-1B played a role in the preferential activation of STAT3 in cav-1(-/-) fibroblasts. Genetic deletion of STAT3 by siRNA modulated the expression of genes involved in cell proliferation and fibrogenesis. Basal expression of α-smooth muscle actin was prominent in cav-1(-/-) liver and kidney, consistent with deposition of collagen in these organs. Collectively, we demonstrate that the antiproliferative and antifibrogenic properties of caveolin-1 in vitro are mediated by the balance between STAT1 and STAT3 activation. Deregulated STAT signaling associated with caveolin-1 deficiency may be relevant to proliferative disorders such as tissue fibrosis.
authors.affiliation: a Division of Pulmonary and Critical Care Medicine, Brigham Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Ryter
authors.forename: Augustine M K
authors.initials: AM
authors.lastname: Choi
authors.forename: Hong Pyo
authors.initials: HP
authors.lastname: Kim
mesh_terms: D000818:Animals; D051242:Caveolin 1 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005355:Fibrosis / Q000378:metabolism* / Q000473:pathology; D053614:Janus Kinase 2 / Q000378:metabolism; D008168:Lung / Q000166:cytology; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D053634:TYK2 Kinase / Q000378:metabolism
chemical_list: D051242:Caveolin 1; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D053634:TYK2 Kinase; C499356:Tyk2 protein, mouse
keywords: antifibrogenic; antifibrogène; caveolin-1; cavéoline-1; lipid raft; protein tyrosine phosphatae-1B; protéine tyrosine phosphatase-1B; radeau lipidique; signal transducers and activators of transcription; transducteur de signaux et activateurs de la transcription