title: Modulation of 17β-Estradiol Signaling on Cellular Proliferation by Caveolin-2.
abstract: The sex hormone 17β-estradiol (E2) exerts pleiotropic effects by binding to the ligand-activated transcription factor estrogen receptor α (ERα). The E2:ERα complex regulates several physiological processes, including cell survival and proliferation, through transcriptional effects (i.e., estrogen responsive element [ERE]-based gene transcription) and non-transcriptional membrane-initiated effects (i.e., the activation of extra-nuclear signaling cascades), which derive from the activation of the pool of ERα that is localized to plasma membrane caveolae. Caveolae are ω-shaped membrane sub-domains that are composed of scaffold proteins named caveolins (i.e., caveolin-1, caveolin-2, and caveolin-3). Although caveolin-3 is exclusively expressed in muscles, caveolin-1 and caveolin-2 are co-expressed in all human tissues. From a functional point of view, caveolin-2 can operate both dependently on and independently of caveolin-1, which is the main coat component of caveolae. Interestingly, while a functional interplay between caveolin-1 and ERα has been reported in the control of E2-induced physiological effects, the role of caveolin-2 in E2:ERα signaling within the cell remains poorly understood. This study shows that siRNA-mediated caveolin-2 depletion in breast ductal carcinoma cells (MCF-7) reduces E2-induced ERα phosphorylation at serine residue 118 (S118), controls intracellular receptor levels, precludes ERα-mediated extra-nuclear activation of signaling pathways, reduces ERα transcriptional activity, and prevents cellular proliferation. Meanwhile, the impact of caveolin-1 depletion on ERα signaling in MCF-7 cells is shown to be similar to that elicited by siRNA-mediated caveolin-2 depletion. Altogether, these data demonstrate that caveolin-2 expression is necessary for the control of E2-dependent cellular proliferation.
authors.affiliation: Department of Sciences, Section Biomedical Sciences and Technology, University Roma Tre, Viale Guglielmo Marconi, Rome, Italy.
authors.forename: Pierangela
authors.initials: P
authors.lastname: Totta
authors.affiliation: Department of Sciences, Section Biomedical Sciences and Technology, University Roma Tre, Viale Guglielmo Marconi, Rome, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Gionfra
authors.affiliation: Department of Sciences, Section Biomedical Sciences and Technology, University Roma Tre, Viale Guglielmo Marconi, Rome, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Busonero
authors.affiliation: Department of Sciences, Section Biomedical Sciences and Technology, University Roma Tre, Viale Guglielmo Marconi, Rome, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Acconcia
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism; D051243:Caveolin 2 / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects*; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D010766:Phosphorylation; D059748:Proteolysis; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: C495540:CAV1 protein, human; C495544:CAV2 protein, human; D051242:Caveolin 1; D051243:Caveolin 2; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004958:Estradiol