Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea.
Department of Medical Science, Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Mol Biol Rep. 2021 Feb;48(2):1651-1658. doi: 10.1007/s11033-021-06179-2. Epub 2021 Feb 12.
SVCT2, Sodium-dependent Vitamin C Transporter 2, uniquely transports ascorbic acid (also known as vitamin C and ascorbate) into all types of cells. Vitamin C is an essential nutrient that must be obtained through the diet and plasma levels are tightly regulated by transporter activity. Vitamin C plays an important role in antioxidant defenses and is a cofactor for many enzymes that enable hormone synthesis, oxygen sensing, collagen synthesis and epigenetic pathways. Although SVCT2 has various functions, regulation of its expression/activity remains poorly understood. We found a p53-binding site, within the SVCT2 promoter, using a transcription factor binding-site prediction tool. In this study, we show that p53 can directly repress SVCT2 transcription by binding a proximal- (-185 to -171 bp) and a distal- (-1800 to -1787 bp) p53-responsive element (PRE), Chromatin immunoprecipitation assays showed that PRE-bound p53 interacts with the corepressor-histone deacetylase 3 (HDAC3), resulting in deacetylation of histones Ac-H4, at the proximal promoter, resulting in transcriptional silencing of SVCT2. Overall, our data suggests that p53 is a potent transcriptional repressor of SVCT2, a critical transporter of diet-derived ascorbic acid, across the plasma membranes of numerous essential tissue cell types.
SVCT2，即钠离子依赖型维生素 C 转运体 2，是唯一能够将抗坏血酸（也称为维生素 C 和抗坏血酸盐）转运进入各种细胞的转运体。维生素 C 是一种必需的营养物质，必须通过饮食获得，而其在血浆中的水平则由转运体的活性严格调节。维生素 C 在抗氧化防御中起着重要作用，并且是许多能够促进激素合成、氧气感应、胶原蛋白合成和表观遗传途径的酶的辅助因子。尽管 SVCT2 具有多种功能，但对其表达/活性的调节仍知之甚少。我们使用转录因子结合位点预测工具，在 SVCT2 启动子中发现了一个 p53 结合位点。在这项研究中，我们表明 p53 可以通过结合近端（-185 至-171bp）和远端（-1800 至-1787bp）p53 反应元件（PRE）直接抑制 SVCT2 转录。染色质免疫沉淀试验表明，PRE 结合的 p53 与核心抑制因子-组蛋白去乙酰化酶 3（HDAC3）相互作用，导致近端启动子处组蛋白 Ac-H4 的去乙酰化，从而导致 SVCT2 的转录沉默。总的来说，我们的数据表明，p53 是 SVCT2 的一种强有力的转录抑制剂，SVCT2 是饮食来源的抗坏血酸穿过许多重要组织细胞类型的质膜的关键转运体。
