Nuclear PTEN functions as an essential regulator of SRF-dependent transcription to control smooth muscle differentiation

Henrick Horita, Christina L. Wysoczynski, Lori A. Walker, Karen S. Moulton, Marcella Li, Allison Ostriker, Rebecca Tucker, Timothy A. McKinsey, Mair E. A. Churchill, Raphael A. Nemenoff and Mary C. M. Weiser-Evans ()
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Henrick Horita: University of Colorado, Anschutz Medical Campus, 12700 East 19th Avenue, C281, Research Complex 2, Room 7101, Aurora, Colorado 80045, USA
Christina L. Wysoczynski: University of Colorado, Anschutz Medical Campus
Lori A. Walker: University of Colorado, Anschutz Medical Campus
Karen S. Moulton: University of Colorado, Anschutz Medical Campus
Marcella Li: University of Colorado, Anschutz Medical Campus
Allison Ostriker: University of Colorado, Anschutz Medical Campus, 12700 East 19th Avenue, C281, Research Complex 2, Room 7101, Aurora, Colorado 80045, USA
Rebecca Tucker: University of Colorado, Anschutz Medical Campus, 12700 East 19th Avenue, C281, Research Complex 2, Room 7101, Aurora, Colorado 80045, USA
Timothy A. McKinsey: University of Colorado, Anschutz Medical Campus
Mair E. A. Churchill: University of Colorado, Anschutz Medical Campus
Raphael A. Nemenoff: University of Colorado, Anschutz Medical Campus, 12700 East 19th Avenue, C281, Research Complex 2, Room 7101, Aurora, Colorado 80045, USA
Mary C. M. Weiser-Evans: University of Colorado, Anschutz Medical Campus, 12700 East 19th Avenue, C281, Research Complex 2, Room 7101, Aurora, Colorado 80045, USA

Nature Communications, 2016, vol. 7, issue 1, 1-17

Abstract: Abstract Vascular disease progression is associated with marked changes in vascular smooth muscle cell (SMC) phenotype and function. SMC contractile gene expression and, thus differentiation, is under direct transcriptional control by the transcription factor, serum response factor (SRF); however, the mechanisms dynamically regulating SMC phenotype are not fully defined. Here we report that the lipid and protein phosphatase, PTEN, has a novel role in the nucleus by functioning as an indispensible regulator with SRF to maintain the differentiated SM phenotype. PTEN interacts with the N-terminal domain of SRF and PTEN–SRF interaction promotes SRF binding to essential promoter elements in SM-specific genes. Factors inducing phenotypic switching promote loss of nuclear PTEN through nucleo-cytoplasmic translocation resulting in reduced myogenically active SRF, but enhanced SRF activity on target genes involved in proliferation. Overall decreased expression of PTEN was observed in intimal SMCs of human atherosclerotic lesions underlying the potential clinical importance of these findings.

Date: 2016
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DOI: 10.1038/ncomms10830

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