Abstract Transcriptional factor p53 is a master regulator of energy metabolism. Energy metabolism strongly depends on thiamine (vitamin B1) and/or its natural derivatives. Thiamine diphosphate (ThDP), which is a major thiamine derivative, affects p53 binding to DNA. In order to elucidate the mechanism of regulation of thiamine-dependent metabolism by p53, we assessed putative p53-binding sites near transcription starting points in genes coding for transporters and enzymes, whose function is associated with thiamine and/or its derivatives. The predictions were validated by studying cell metabolic response to the p53 inducer cisplatin. Expression of p53 and its known target, p21, has been evaluated in cisplatin-treated and control human lung adenocarcinoma A549 cells that possess functional p53 pathway. We also investigated the activity of enzymes involved in the thiamine-dependent energy metabolism. Along with upregulating the expression of p53 and p21, cisplatin affected the activities of metabolic enzymes, whose genes were predicted as carrying the p53-binding sites. The activity of glutamate dehydrogenase GDH2 isoenzyme strongly decreased, while the activities of NADP + -dependent isocitrate dehydrogenase (IDH) and malic enzymes, as well as the activity of 2-oxoglutarate dehydrogenase complex at its endogenous ThDP level, were elevated. Simultaneously, the activities of NAD + -dependent IDH, mitochondrial aspartate aminotransferase, and two malate dehydrogenase isoenzymes, whose genes were not predicted to have the p53-binding sequences near the transcription starting points, were upregulated by cisplatin. The p53-dependent regulation of the assayed metabolic enzymes correlated with induction of p21 by p53 rather than induction of p53 itself.

中文翻译：

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p53 对哺乳动物中硫胺素（维生素 B1）依赖性代谢的调节

摘要 转录因子 p53 是能量代谢的主要调节因子。能量代谢强烈依赖硫胺素（维生素 B1）和/或其天然衍生物。硫胺素二磷酸 (ThDP) 是一种主要的硫胺素衍生物，会影响 p53 与 DNA 的结合。为了阐明 p53 调节硫胺素依赖性代谢的机制，我们评估了编码转运蛋白和酶的基因中转录起点附近的假定 p53 结合位点，其功能与硫胺素和/或其衍生物相关。通过研究细胞对 p53 诱导剂顺铂的代谢反应来验证预测。p53 及其已知靶标 p21 的表达已在具有功能性 p53 通路的顺铂处理和对照人肺腺癌 A549 细胞中进行了评估。我们还研究了参与硫胺素依赖性能量代谢的酶的活性。随着 p53 和 p21 的表达上调，顺铂影响代谢酶的活性，这些酶的基因被预测为携带 p53 结合位点。谷氨酸脱氢酶 GDH2 同工酶的活性强烈降低，而 NADP + 依赖性异柠檬酸脱氢酶 (IDH) 和苹果酸酶的活性，以及​​ 2-酮戊二酸脱氢酶复合物在内源性 ThDP 水平上的活性升高。同时，顺铂上调了 NAD + 依赖性 IDH、线粒体天冬氨酸氨基转移酶和两种苹果酸脱氢酶同工酶的活性，这些酶的基因预计在转录起点附近没有 p53 结合序列。