Back to Search
Start Over
NF-κB and GATA-Binding Factor 6 Repress Transcription of Caveolins in Bladder Smooth Muscle Hypertrophy.
- Source :
-
The American journal of pathology [Am J Pathol] 2019 Apr; Vol. 189 (4), pp. 847-867. Date of Electronic Publication: 2019 Jan 30. - Publication Year :
- 2019
-
Abstract
- Caveolins (CAVs) are structural proteins of caveolae that function as signaling platforms to regulate smooth muscle contraction. Loss of CAV protein expression is associated with impaired contraction in obstruction-induced bladder smooth muscle (BSM) hypertrophy. In this study, microarray analysis of bladder RNA revealed down-regulation of CAV1, CAV2, and CAV3 gene transcription in BSM from models of obstructive bladder disease in mice and humans. We identified and characterized regulatory regions responsible for CAV1, CAV2, and CAV3 gene expression in mice with obstruction-induced BSM hypertrophy, and in men with benign prostatic hyperplasia. DNA affinity chromatography and chromatin immunoprecipitation assays revealed a greater increase in binding of GATA-binding factor 6 (GATA-6) and NF-κB to their cognate binding motifs on CAV1, CAV2, and CAV3 promoters in obstructed BSM relative to that observed in control BSM. Knockout of NF-κB subunits, shRNA-mediated knockdown of GATA-6, or pharmacologic inhibition of GATA-6 and NF-κB in BSM increased CAV1, CAV2, and CAV3 transcription and promoter activity. Conversely, overexpression of GATA-6 decreased CAV2 and CAV3 transcription and promoter activity. Collectively, these data provide new insight into the mechanisms by which CAV gene expression is repressed in hypertrophied BSM in obstructive bladder disease.<br /> (Copyright © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Aged
Animals
Biomarkers analysis
Caveolins genetics
Caveolins metabolism
GATA6 Transcription Factor genetics
Gene Expression Profiling
Gene Expression Regulation
Humans
Hypertrophy etiology
Hypertrophy metabolism
Male
Mice
Mice, Inbred C57BL
Middle Aged
Muscle Contraction
Muscle, Smooth metabolism
NF-kappa B genetics
Prostatic Hyperplasia metabolism
Prostatic Hyperplasia pathology
Urinary Bladder Neck Obstruction surgery
Caveolins antagonists & inhibitors
GATA6 Transcription Factor metabolism
Hypertrophy pathology
Muscle, Smooth pathology
NF-kappa B metabolism
Transcription, Genetic
Urinary Bladder Neck Obstruction complications
Subjects
Details
- Language :
- English
- ISSN :
- 1525-2191
- Volume :
- 189
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- The American journal of pathology
- Publication Type :
- Academic Journal
- Accession number :
- 30707892
- Full Text :
- https://doi.org/10.1016/j.ajpath.2018.12.013