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PTEN-dependent regulation of SRF transcriptional activity and SMC phenotype control

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? DESCRIPTION (provided by applicant): A unique characteristic of resident vascular smooth muscle cells (SMCs) and a hallmark of vascular disease progression is SMC phenotypic switching marked by a change in SMC phenotype. Regulation of PTEN, a lipid and protein phosphatase that predominantly inhibits cytoplasmic PI3K/Akt activity, is critical in pathological vascular remodeling. PTEN represses SMC phenotypic switching while its loss results in decreased SM contractile gene expression and increased proliferation and production inflammatory mediators. Enhanced proliferation and inflammatory mediator production are dependent on loss of PTEN's phosphatase activity and consequent increased Akt activity. However, since SM genes are under direct transcriptional control by serum response factor (SRF), the mechanism underlying PTEN's regulation of SM gene expression remained unclear and is the focus of this proposal. Under physiological conditions, SMCs express a quiescent, differentiated phenotype, characterized by high expression of SRF-dependent SM genes. SRF is a ubiquitous and essential transcription factor that binds CArG elements in SM genes. Paradoxically, SRF also regulates immediate early genes. Control of SM gene expression by SRF involves interactions between SRF and cell-specific co- activators, epigenetic control of gene expression, and regulation of SRF through post-translational modifications and spatial/temporal changes. Our new published and preliminary data show a direct link between PTEN and SRF in this regulation. Our published studies demonstrated that PTEN is a downstream effector of SRF through a microRNA (miRNA)-dependent pathway. Loss of this axis promotes reprogramming to a proliferative, inflammatory phenotype. To support this current project, new preliminary data suggest a novel upstream function for nuclear PTEN that is independent of its phosphatase activity. We demonstrate direct interaction of PTEN with SRF, which facilitates SRF-dependent SM gene transcription suggesting a positive feedback loop involving PTEN and SRF. Pathophysiologic or genetic loss of PTEN results in loss of SRF binding to SM gene promoters and SMC phenotypic switching. Clinically, loss of nuclear PTEN and overall decreased expression is observed in intimal SMCs of human atherosclerotic lesions, supporting a critical role for nuclear PTEN in regulation of lesion progression. We propose a positive feedback loop between PTEN and SRF underlies maintenance of a differentiated, quiescent SMC phenotype. We hypothesize that physiologic or pathologic stimuli induce nuclear exclusion of PTEN and SRF with subsequent inhibition of SRF- dependent SM gene transcription and dysregulation of the SRF-miRNA-PTEN network controlling proliferation and inflammation. We will define the molecular mechanisms underlying PTEN regulation of SRF transcriptional activity (Aim One), establish the importance of PTEN-dependent regulation of SRF transcriptional activity using complex genetic mouse models of atherosclerosis and vascular injury (Aim Two), and establish the significance of nuclear PTEN on SMC phenotype in normal and diseased human arteries (Aim Three).
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