Zhang Xiaomin, Azhar Gohar, Wei Jeanne Y
Donald W. Reynolds Institute on Aging, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
PLoS One. 2017 Dec 21;12(12):e0190011. doi: 10.1371/journal.pone.0190011. eCollection 2017.
The sirtuin proteins are an evolutionarily conserved family of NAD+-dependent deacetylases that regulate various cellular functions. Among the seven sirtuins, SIRT2 is predominantly found in the cytoplasm, and is present in a wide range of tissues. Recent studies indicate that SIRT2 plays an important role in metabolic homeostasis. Several studies indicate that SIRT2 is upregulated under serum deprivation conditions. Since the serum response factor gene usually responds rapidly to serum deprivation and/or serum restoration following deprivation, we hypothesized that a common mechanism may serve to regulate both SIRT2 and SRF during serum stimulation. Using a bioinformatics approach, we searched the SRF binding motif in the SIRT2 gene, and found one classic CArG element (CCATAATAGG) in the SIRT2 gene promoter, which was bound to SRF in the electrophoretic mobility shift assay (EMSA). Serum deprivation induced SIRT2 expression, while SRF and the SRF binding protein, p49/STRAP, repressed SIRT2 gene expression. SIRT2 gene expression was also repressed by the Rho/SRF inhibitor, CCG-1423. These data demonstrate that the classic SRE element in the SIRT2 gene promoter region is functional and therefore, SIRT2 gene is a downstream target of the Rho/SRF signaling pathway. The increased expression of SRF that was observed in the aged heart may affect SIRT2 gene expression and contribute to altered metabolic status in senescence.
沉默调节蛋白是一类进化上保守的烟酰胺腺嘌呤二核苷酸（NAD⁺）依赖性脱乙酰酶家族，可调节多种细胞功能。在七种沉默调节蛋白中，SIRT2主要存在于细胞质中，且在多种组织中都有表达。最近的研究表明，SIRT2在代谢稳态中起重要作用。多项研究表明，在血清剥夺条件下SIRT2表达上调。由于血清反应因子基因通常对血清剥夺和/或剥夺后的血清恢复反应迅速，我们推测在血清刺激过程中可能存在一种共同机制来调节SIRT2和血清反应因子（SRF）。我们采用生物信息学方法，在SIRT2基因中搜索SRF结合基序，在SIRT2基因启动子中发现了一个经典的CArG元件（CCATAATAGG），在电泳迁移率变动分析（EMSA）中它与SRF结合。血清剥夺诱导SIRT2表达，而SRF和SRF结合蛋白p49/STRAP抑制SIRT2基因表达。Rho/SRF抑制剂CCG - 1423也可抑制SIRT2基因表达。这些数据表明，SIRT2基因启动子区域的经典血清反应元件（SRE）具有功能，因此，SIRT2基因是Rho/SRF信号通路的下游靶点。在老年心脏中观察到的SRF表达增加可能会影响SIRT2基因表达，并导致衰老过程中代谢状态的改变。
