NF-κB and GATA-Binding Factor 6 Repress Transcription of Caveolins in Bladder Smooth Muscle Hypertrophy.

Authors

• Chellappagounder Thangavel
• Cristiano M Gomes
• Stephen A Zderic
• Elham Javed
• Sankar Addya
• Jagmohan Singh
• Sreya Das
• Ruth Birbe
• Robert B Den
• Satish Rattan
• Deepak A Deshpande
• Raymond B Penn
• Samuel Chacko
• Ettickan Boopathi

Publication/Presentation Date

4-1-2019

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.

Volume

189

Issue

4

First Page

847

Last Page

867

ISSN

1525-2191

Published In/Presented At

Thangavel, C., Gomes, C. M., Zderic, S. A., Javed, E., Addya, S., Singh, J., Das, S., Birbe, R., Den, R. B., Rattan, S., Deshpande, D. A., Penn, R. B., Chacko, S., & Boopathi, E. (2019). NF-κB and GATA-Binding Factor 6 Repress Transcription of Caveolins in Bladder Smooth Muscle Hypertrophy. The American journal of pathology, 189(4), 847–867. https://doi.org/10.1016/j.ajpath.2018.12.013

Disciplines

Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods

PubMedID

30707892

Department(s)

Administration and Leadership

Document Type

Article