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

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-kB to their cognate binding motifs on CAV1, CAV2, and CAV3 promoters in obstructed BSM relative to that observed in control BSM. Knockout of NF-kB subunits, shRNA-mediated knockdown of GATA-6, or pharmacologic inhibition of GATA-6 and NF-kB 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.

Discovered Key CpG Sites by Analyzing DNA Methylation and Gene Expression in Breast Cancer Samples

“…In all types of lung cancer, CAV2 is dysregulated at the RNA and protein levels (Wikman et al, 2004). Experiments have verified that the CAV2 gene transcription is downregulated in mice and humans with obstructive bladder disease (Thangavel et al, 2019). Studies have confirmed that compared with the corresponding normal tissues, the mRNA level of CAV2 in human breast cancer tissues is significantly down-regulated (p < 0.001) (Sagara et al, 2004).…”

Caveolin-1 Regulates Cellular Metabolism: A Potential Therapeutic Target in Kidney Disease

“…Therefore, the increase in intracellular free cholesterol can regulate the mRNA expression of CAV1 by stimulating the binding of SRE-binding protein 1 (SPEBP-1) to the cholesterol regulatory element in the CAV1 promoter (Bist et al, 1997). Other transcription factors, including P53 (Bist et al, 2000), c-myc (Xie et al, 2003), GAT-binding factor 6 (GAT-6) (Boopathi et al, 2011), NF-κB (Thangavel et al, 2019), forkhead box O (FoxO) (van den Heuvel et al, 2005), and FoxM1 (Huang et al, 2012), can also bind to the related E-BOX of the promoter of the CAV1 and regulate its transcription. These findings suggest that the Cav-1 may have a potential regulatory role in cellular metabolism, inflammation, and fibrosis.…”

The Potential Contribution of Caveolin 1 to HIV Latent Infection

“…In diabetes and ozone injury [116] models, Cav-1 negatively regulates PI3K signaling, a signaling that prevents latency by the activation of NF-κB p65. The expression of Cav-1 itself is prevented by the activation of NF-κB [117]. In macrophages, Cav-1 association with TLR4 prevents pro-inflammatory cytokine production [114] that could add to the viral replication by further activation of NF-κB.…”