High rates of glycolysis in cancer cells are a well-established characteristic of many human tumors, providing rapidly proliferating cancer cells with metabolites that can be used as precursors for anabolic pathways. Maintenance of high glycolytic rates depends on the lactate dehydrogenase-catalyzed regeneration of NAD+ from GAPDH-generated NADH because an increased NADH:NAD+ ratio inhibits GAPDH. Here, using human breast cancer cell models, we identified a pathway in which changes in the extramitochondrial-free NADH:NAD+ ratio signaled through the CtBP family of NADH-sensitive transcriptional regulators to control the abundance and activity of p53. NADH-free forms of CtBPs cooperated with the p53-binding partner HDM2 to suppress p53 function, and loss of these forms in highly glycolytic cells resulted in p53 accumulation. We propose that this pathway represents a "glycolytic stress response" in which the initiation of a protective p53 response by an increased NADH:NAD+ ratio enables cells to avoid cellular damage caused by mismatches between metabolic supply and demand.

中文翻译：

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p53 在癌细胞中受 NADH 依赖性转录调节因子的 CtBP 家族的有氧糖酵解调节。

癌细胞中的高糖酵解率是许多人类肿瘤的公认特征，它为快速增殖的癌细胞提供了可用作合成代谢途径前体的代谢物。维持高糖酵解速率取决于乳酸脱氢酶催化的 NAD+ 从 GAPDH 产生的 NADH 的再生，因为增加的 NADH:NAD+ 比率会抑制 GAPDH。在这里，使用人类乳腺癌细胞模型，我们确定了一种途径，其中线粒体外游离 NADH：NAD+ 比率的变化通过 NADH 敏感转录调节因子的 CtBP 家族发出信号，以控制 p53 的丰度和活性。不含 NADH 的 CtBPs 形式与 p53 结合伙伴 HDM2 合作以抑制 p53 功能，并且在高度糖酵解细胞中这些形式的丧失导致 p53 积累。