Downregulated REST Transcription Factor Is a Switch Enabling Critical Potassium Channel Expression and Cell Proliferation

Abstract

Induction of K(Ca)3.1 (IKCa) potassium channel plays an important role in vascular smooth muscle cell proliferation. Here, we report that the gene encoding K(Ca)3.1 (KCNN4) contains a functional repressor element 1-silencing transcription factor (REST or NRSF) binding site and is repressed by REST. Although not previously associated with vascular smooth muscle cells, REST is present and recruited to the KCNN4 gene in situ. Significantly, expression of REST declines when there is cellular proliferation, showing an inverse relationship with functional K(Ca)3.1. Downregulated REST and upregulated K(Ca)3.1 are also evident in smooth muscle cells of human neointimal hyperplasia grown in organ culture. Furthermore, inhibition of K(Ca)3.1 suppresses neointimal formation, and exogenous REST reduces the functional impact of K(Ca)3.1. Here, we show REST plays a previously unrecognized role as a switch regulating potassium channel expression and consequently the phenotype of vascular smooth muscle cells and human vascular disease.

Functional significance of repressor element 1 silencing transcription factor (REST) target genes in pancreatic beta cells

“…In these mice, the expression of REST did not alter the architecture of pancreatic islets, but induced a reduction in the number of beta cells. This effect is consistent with the anti-proliferative action of REST, previously reported in tumoral transformation [41] and human neointimal hyperplasia [9]. The reduced number of cells correlated with reduced expression of the insulin gene and lower pancreatic content of the hormone, which was not observed in INS1-E cells acutely transduced for REST.…”

“…Previous reports have identified some of these target genes and their function in and outside the nervous system. Thus, it is now documented that REST target genes are involved in the reactivation of the fetal cardiac gene programme in hypertrophied and failing hearts [8], and modulate the vascular plasticity/remodelling of human neointimal hyperplasia [9].…”

Loss of the repressor REST in uterine fibroids promotes aberrant G protein-coupled receptor 10 expression and activates mammalian target of rapamycin pathway

“…Overexpression of alternatively spliced forms of REST that function as dominant negatives has also been shown to promote tumorigenesis (26,27). Importantly, down-regulation of REST has been shown to enable gene expression that promotes vascular SMC proliferation (43). The role of REST in myometrial SMCs or its loss in the pathogenesis of uterine fibroids has not been reported previously.…”

Renal fibrosis is attenuated by targeted disruption of K Ca 3.1 potassium channels

“…Whereas the first directly mediate Ca 2ϩ inflow, the latter regulate membrane potential and thus provide the driving force for Ca 2ϩ entry (13). In particular, the intermediate-conductance K Ca (K Ca 3.1) has been shown to play an important role in promoting mitogenesis in several tissues such as the endothelium (15,16), vascular smooth muscle (17)(18)(19), and T lymphocytes (20) as well as in several cell lines including A7r5 neonatal aortic smooth muscle cells (21), 10T1/2-MRF4 myogenic fibroblasts (22,23), HMEC-1 dermal endothelial cells (15), and some cancer cell lines (24,25).…”