Horita Henrick, Wysoczynski Christina L, Walker Lori A, Moulton Karen S, Li Marcella, Ostriker Allison, Tucker Rebecca, McKinsey Timothy A, Churchill Mair E A, Nemenoff Raphael A, Weiser-Evans Mary C M
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 Pharmacology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado 80045, USA.
Nat Commun. 2016 Mar 4;7:10830. doi: 10.1038/ncomms10830.
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.
血管疾病进展与血管平滑肌细胞（SMC）表型和功能的显著变化相关。SMC收缩基因的表达以及由此产生的分化受转录因子血清反应因子（SRF）的直接转录控制；然而，动态调节SMC表型的机制尚未完全明确。在此我们报告，脂质和蛋白质磷酸酶PTEN在细胞核中具有新作用，它作为SRF不可或缺的调节因子，维持分化的平滑肌表型。PTEN与SRF的N端结构域相互作用，PTEN-SRF相互作用促进SRF与平滑肌特异性基因中的必需启动子元件结合。诱导表型转换的因素通过核质转运促进核PTEN的丢失，导致肌源性活性SRF减少，但SRF对参与增殖的靶基因的活性增强。在人类动脉粥样硬化病变的内膜平滑肌细胞中观察到PTEN的整体表达下降，这些发现具有潜在的临床重要性。
