Downregulated REST transcription factor is a switch enabling critical potassium channel expression and cell proliferation

Alex Cheong; Andrew J Bingham; Jing Li; Bhaskar Kumar; Piruthivi Sukumar; Christopher Munsch; Noel J Buckley; Craig B Neylon; Karen E Porter; David J Beech; Ian C Wood

doi:10.1016/j.molcel.2005.08.030

Downregulated REST transcription factor is a switch enabling critical potassium channel expression and cell proliferation

Alex Cheong, Andrew J Bingham, Jing Li, Bhaskar Kumar, Piruthivi Sukumar, Christopher Munsch, Noel J Buckley, Craig B Neylon, Karen E Porter, David J Beech, Ian C Wood

Aston Pharmacy School

Research output: Contribution to journal › Article › peer-review

Abstract

Induction of K_Ca3.1 (IKCa) potassium channel plays an important role in vascular smooth muscle cell proliferation. Here, we report that the gene encoding K_Ca3.1 (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_Ca3.1. Downregulated REST and upregulated K_Ca3.1 are also evident in smooth muscle cells of human neointimal hyperplasia grown in organ culture. Furthermore, inhibition of K_Ca3.1 suppresses neointimal formation, and exogenous REST reduces the functional impact of K_Ca3.1. 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.

Original language	English
Pages (from-to)	45-52
Number of pages	8
Journal	Molecular Cell
Volume	20
Issue number	1
DOIs	https://doi.org/10.1016/j.molcel.2005.08.030
Publication status	Published - 7 Oct 2005

Keywords

Animals
Blood Vessels/metabolism
Cell Line
Cell Proliferation
Co-Repressor Proteins
DNA-Binding Proteins/genetics
Down-Regulation/physiology
Humans
Hyperplasia/metabolism
Intermediate-Conductance Calcium-Activated Potassium Channels/biosynthesis
Male
Mice
Myocytes, Smooth Muscle/metabolism
Nerve Tissue Proteins/genetics
Organ Culture Techniques/methods
Repressor Proteins/genetics
Response Elements/physiology
Up-Regulation/physiology

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10.1016/j.molcel.2005.08.030

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title = "Downregulated REST transcription factor is a switch enabling critical potassium channel expression and cell proliferation",

abstract = "Induction of KCa3.1 (IKCa) potassium channel plays an important role in vascular smooth muscle cell proliferation. Here, we report that the gene encoding KCa3.1 (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 KCa3.1. Downregulated REST and upregulated KCa3.1 are also evident in smooth muscle cells of human neointimal hyperplasia grown in organ culture. Furthermore, inhibition of KCa3.1 suppresses neointimal formation, and exogenous REST reduces the functional impact of KCa3.1. 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.",

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author = "Alex Cheong and Bingham, {Andrew J} and Jing Li and Bhaskar Kumar and Piruthivi Sukumar and Christopher Munsch and Buckley, {Noel J} and Neylon, {Craig B} and Porter, {Karen E} and Beech, {David J} and Wood, {Ian C}",

year = "2005",

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day = "7",

doi = "10.1016/j.molcel.2005.08.030",

language = "English",

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T1 - Downregulated REST transcription factor is a switch enabling critical potassium channel expression and cell proliferation

AU - Cheong, Alex

AU - Bingham, Andrew J

AU - Li, Jing

AU - Kumar, Bhaskar

AU - Sukumar, Piruthivi

AU - Munsch, Christopher

AU - Buckley, Noel J

AU - Neylon, Craig B

AU - Porter, Karen E

AU - Beech, David J

AU - Wood, Ian C

PY - 2005/10/7

Y1 - 2005/10/7

N2 - Induction of KCa3.1 (IKCa) potassium channel plays an important role in vascular smooth muscle cell proliferation. Here, we report that the gene encoding KCa3.1 (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 KCa3.1. Downregulated REST and upregulated KCa3.1 are also evident in smooth muscle cells of human neointimal hyperplasia grown in organ culture. Furthermore, inhibition of KCa3.1 suppresses neointimal formation, and exogenous REST reduces the functional impact of KCa3.1. 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.

AB - Induction of KCa3.1 (IKCa) potassium channel plays an important role in vascular smooth muscle cell proliferation. Here, we report that the gene encoding KCa3.1 (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 KCa3.1. Downregulated REST and upregulated KCa3.1 are also evident in smooth muscle cells of human neointimal hyperplasia grown in organ culture. Furthermore, inhibition of KCa3.1 suppresses neointimal formation, and exogenous REST reduces the functional impact of KCa3.1. 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.

KW - Animals

KW - Blood Vessels/metabolism

KW - Cell Line

KW - Cell Proliferation

KW - Co-Repressor Proteins

KW - DNA-Binding Proteins/genetics

KW - Down-Regulation/physiology

KW - Humans

KW - Hyperplasia/metabolism

KW - Intermediate-Conductance Calcium-Activated Potassium Channels/biosynthesis

KW - Male

KW - Mice

KW - Myocytes, Smooth Muscle/metabolism

KW - Nerve Tissue Proteins/genetics

KW - Organ Culture Techniques/methods

KW - Repressor Proteins/genetics

KW - Response Elements/physiology

KW - Up-Regulation/physiology

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SN - 1097-2765

VL - 20

SP - 45

EP - 52

JO - Molecular Cell

JF - Molecular Cell

IS - 1

ER -

Downregulated REST transcription factor is a switch enabling critical potassium channel expression and cell proliferation

Abstract

Keywords

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