title: Transcriptional repression of Caveolin-1 (CAV1) gene expression by GATA-6 in bladder smooth muscle hypertrophy in mice and human beings.
abstract: Hypertrophy occurs in urinary bladder wall smooth muscle (BSM) in men with partial bladder outlet obstruction (PBOO) caused by benign prostatic hyperplasia (BPH) and in animal models of PBOO. Hypertrophied BSM from the rabbit model exhibits down-regulation of caveolin-1, a structural and functional protein of caveolae that function as signaling platforms to mediate interaction between receptor proteins and adaptor and effector molecules to regulate signal generation, amplification, and diversification. Caveolin-1 expression is diminished in PBOO-induced BSM hypertrophy in mice and in men with BPH. The proximal promoter of the human and mouse caveolin-1 (CAV1) gene was characterized, and it was observed that the transcription factor GATA-6 binds this promoter, causing reduced expression of caveolin-1. Furthermore, caveolin-1 expression levels inversely correlate with the abundance of GATA-6 in BSM hypertrophy in mice and human beings. Silencing of GATA6 gene expression up-regulates caveolin-1 expression, whereas overexpression of GATA-6 protein sustains the transcriptional repression of caveolin-1 in bladder smooth muscle cells. Together, these data suggest that GATA-6 acts as a transcriptional repressor of CAV1 gene expression in PBOO-induced BSM hypertrophy in men and mice. GATA-6-induced transcriptional repression represents a new regulatory mechanism of CAV1 gene expression in pathologic BSM, and may serve as a target for new therapy for BPH-induced bladder dysfunction in aging men.
authors.affiliation: Division of Urology, University of Pennsylvania, Glenolden, Pennsylvania, USA.
authors.forename: Ettickan
authors.initials: E
authors.lastname: Boopathi
authors.forename: Cristiano Mendes
authors.initials: CM
authors.lastname: Gomes
authors.forename: Robert
authors.initials: R
authors.lastname: Goldfarb
authors.forename: Mary
authors.initials: M
authors.lastname: John
authors.forename: Vittala Gopal
authors.initials: VG
authors.lastname: Srinivasan
authors.forename: Jaber
authors.initials: J
authors.lastname: Alanzi
authors.forename: S Bruce
authors.initials: SB
authors.lastname: Malkowicz
authors.forename: Hasmeena
authors.initials: H
authors.lastname: Kathuria
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Zderic
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Wein
authors.forename: Samuel
authors.initials: S
authors.lastname: Chacko
mesh_terms: D000368:Aged; D000818:Animals; D015153:Blotting, Western; D051242:Caveolin 1 / Q000096:biosynthesis* / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D050993:GATA6 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D006984:Hypertrophy; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018613:Microscopy, Confocal; D008875:Middle Aged; D009130:Muscle, Smooth / Q000378:metabolism / Q000473:pathology*; D011401:Promoter Regions, Genetic; D011470:Prostatic Hyperplasia / Q000150:complications; D020133:Reverse Transcriptase Polymerase Chain Reaction; D001745:Urinary Bladder Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001748:Urinary Bladder Neck Obstruction / Q000209:etiology / Q000235:genetics / Q000473:pathology
chemical_list: C495540:CAV1 protein, human; D051242:Caveolin 1; D050993:GATA6 Transcription Factor