title: 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.
authors.affiliation: Institute of Membrane and Systems Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom.
authors.forename: Alex
authors.initials: A
authors.lastname: Cheong
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Bingham
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Kumar
authors.forename: Piruthivi
authors.initials: P
authors.lastname: Sukumar
authors.forename: Christopher
authors.initials: C
authors.lastname: Munsch
authors.forename: Noel J
authors.initials: NJ
authors.lastname: Buckley
authors.forename: Craig B
authors.initials: CB
authors.lastname: Neylon
authors.forename: Karen E
authors.initials: KE
authors.lastname: Porter
authors.forename: David J
authors.initials: DJ
authors.lastname: Beech
authors.forename: Ian C
authors.initials: IC
authors.lastname: Wood
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D049109:Cell Proliferation; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology*; D006801:Humans; D006965:Hyperplasia / Q000378:metabolism / Q000473:pathology; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009924:Organ Culture Techniques / Q000379:methods; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology
chemical_list: D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; D009419:Nerve Tissue Proteins; C121019:RCOR1 protein, human; D012097:Repressor Proteins