title: Nuclear PTEN functions as an essential regulator of SRF-dependent transcription to control smooth muscle differentiation.
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.
authors.affiliation: Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado, Anschutz Medical Campus, 12700 East 19th Avenue, C281, Research Complex 2, Room 7101, Aurora, Colorado 80045, USA.
authors.forename: Henrick
authors.initials: H
authors.lastname: Horita
authors.affiliation: Department of Pharmacology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado 80045, USA.
authors.forename: Christina L
authors.initials: CL
authors.lastname: Wysoczynski
authors.affiliation: Department of Medicine, Division of Cardiology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado 80045, USA.
authors.forename: Lori A
authors.initials: LA
authors.lastname: Walker
authors.affiliation: Department of Medicine, Division of Cardiology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado 80045, USA.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Moulton
authors.affiliation: Department of Medicine, Division of Cardiology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado 80045, USA.
authors.forename: Marcella
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado, Anschutz Medical Campus, 12700 East 19th Avenue, C281, Research Complex 2, Room 7101, Aurora, Colorado 80045, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Ostriker
authors.affiliation: Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado, Anschutz Medical Campus, 12700 East 19th Avenue, C281, Research Complex 2, Room 7101, Aurora, Colorado 80045, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Tucker
authors.affiliation: Department of Medicine, Division of Cardiology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado 80045, USA.|Center for Fibrosis Research and Translation, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado 80045, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: McKinsey
authors.affiliation: Department of Pharmacology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado 80045, USA.
authors.forename: Mair E A
authors.initials: ME
authors.lastname: Churchill
authors.affiliation: Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado, Anschutz Medical Campus, 12700 East 19th Avenue, C281, Research Complex 2, Room 7101, Aurora, Colorado 80045, USA.|Department of Medicine, Cardiovascular Pulmonary Research Program, University of Colorado, Anschutz Medical Campus, Aurora, Colorado 80045, USA.
authors.forename: Raphael A
authors.initials: RA
authors.lastname: Nemenoff
authors.affiliation: Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado, Anschutz Medical Campus, 12700 East 19th Avenue, C281, Research Complex 2, Room 7101, Aurora, Colorado 80045, USA.|Center for Fibrosis Research and Translation, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado 80045, USA.|Department of Medicine, Cardiovascular Pulmonary Research Program, University of Colorado, Anschutz Medical Campus, Aurora, Colorado 80045, USA.
authors.forename: Mary C M
authors.initials: MC
authors.lastname: Weiser-Evans
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D026362:Serum Response Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D026362:Serum Response Factor; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse