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Purine-rich element binding protein B attenuates the coactivator function of myocardin by a novel molecular mechanism of smooth muscle gene repression

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Abstract

Myocardin is a potent transcriptional coactivator protein, which functions as the master regulator of vascular smooth muscle cell differentiation. The cofactor activity of myocardin is mediated by its physical interaction with serum response factor, a ubiquitously expressed transactivator that binds to CArG boxes in genes encoding smooth muscle-restricted proteins. Purine-rich element binding protein B (Purβ) represses the transcription of the smooth muscle α-actin gene (Acta2) in fibroblasts and smooth muscle cells by interacting with single-stranded DNA sequences flanking two 5′ CArG boxes in the Acta2 promoter. In this study, the ability of Purβ to modulate the cofactor activity of myocardin was investigated using a combination of cellular and biochemical approaches. Results of smooth muscle gene promoter-reporter assays indicated that Purβ specifically inhibits the coactivator function of myocardin in a manner requiring the presence of all three single-stranded DNA binding domains in the Purβ homodimer. DNA binding analyses demonstrated that Purβ interacts with CArG-containing DNA elements with a much lower affinity compared to other purine-rich target sequences present in the Acta2 promoter. Co-immunoprecipitation and DNA pull-down assays revealed that Purβ associates with myocardin and serum response factor when free or bound to duplex DNA containing one or more CArG boxes. Functional analysis of engineered Purβ point mutants identified several amino acid residues essential for suppression of myocardin activity. Collectively, these findings suggest an inhibitory mechanism involving direct protein–protein interaction between the homodimeric Purβ repressor and the myocardin-serum response factor-CArG complex.

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Data availability

The data sets used and/or analyzed that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

Purα:

Purine-rich element binding protein A

Purβ:

Purine-rich element binding protein B

SRF:

Serum response factor

Myocd:

Myocardin

ssDNA:

Single-stranded DNA

MCAT:

Muscle-CAT

CArG:

CC(A + T-rich)6GG

MEF:

Mouse embryo fibroblast

VSMC:

Vascular smooth muscle cell

FBS:

Fetal bovine serum

WT:

Wild type

BSA:

Bovine serum albumin

SDS:

Sodium dodecyl sulfate

PAGE:

Polyacrylamide gel electrophoresis

DTT:

Dithiothreitol

PMSF:

Phenylmethylsulfonyl fluoride

ELISA:

Enzyme-linked immunosorbent assay

HRP:

Horseradish peroxidase

TGF-β1:

Transforming growth factor β1

bp:

Base pair

nt:

Nucleotide

h:

Hour

min:

Minute

sec:

Second

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Funding

This study was supported by a Grant from the American Heart Association Founders Affiliate 16GRNT31160006. LAF was supported by an institutional training Grant from the National Heart, Lung, and Blood Institute T32 HL007594.

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Author notes

  1. Lauren A. Ferris

    Present address: Woodstock Union High School, 100 Amsden Way, Woodstock, VT, 05091, USA

Authors and Affiliations

  1. Department of Biochemistry, University of Vermont, Robert Larner, M.D. College of Medicine, Burlington, VT, 05405, USA

    Lauren A. Ferris & Robert J. Kelm Jr.

  2. Department of Medicine, University of Vermont, Robert Larner, M.D. College of Medicine, Burlington, VT, 05405, USA

    Andrea T. Foote, Shu-Xia Wang & Robert J. Kelm Jr.

  3. Division of Cardiovascular Medicine, University of Vermont, Robert Larner, M.D. College of Medicine, Burlington, VT, 05405, USA

    Andrea T. Foote, Shu-Xia Wang & Robert J. Kelm Jr.

  4. Department of Medicine, University of Vermont, Colchester Research Facility, 360 South Park Drive, Colchester, VT, 05446, USA

    Robert J. Kelm Jr.

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Contributions

LAF and RJK conceived and designed the study. LAF, ATF, SXW, and RJK performed experiments and/or analyzed the resulting data. LAF and ATF developed and generated illustrations of protein structure and protein-DNA interaction. LAF, ATF, and RJK wrote and/or edited the manuscript.

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Correspondence to Robert J. Kelm Jr..

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All experiments and procedures involving the use of mice were carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and with the approval of the University of Vermont Institutional Animal Care and Use Committee.

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Ferris, L.A., Foote, A.T., Wang, SX. et al. Purine-rich element binding protein B attenuates the coactivator function of myocardin by a novel molecular mechanism of smooth muscle gene repression. Mol Cell Biochem 476, 2899–2916 (2021). https://doi.org/10.1007/s11010-021-04117-1

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