Downregulated REST transcription factor is a switch enabling critical potassium channel expression and cell proliferation.
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.
Cheong
Alex
A
Institute of Membrane and Systems Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom.
Bingham
Andrew J
AJ
Li
Jing
J
Kumar
Bhaskar
B
Sukumar
Piruthivi
P
Munsch
Christopher
C
Buckley
Noel J
NJ
Neylon
Craig B
CB
Porter
Karen E
KE
Beech
David J
DJ
Wood
Ian C
IC
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
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