Effect of Mutant p53 Proteins on Glycolysis and Mitochondrial Metabolism
Effect of Mutant p53 Proteins on Glycolysis and Mitochondrial Metabolism
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DOI：
10.1128/mcb.00328-17
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发表时间：
2017-12-01
影响因子：
5.3
通讯作者：
Vakifahmetoglu-Norberg, Helin
中科院分区：
文献类型：
--
作者：
Eriksson, Matilda;Ambroise, Gorbatchev;Vakifahmetoglu-Norberg, Helin
TP53是人类癌症中最常见的突变基因之一。与其他经常缺失或获得功能丧失突变的肿瘤抑制因子不同，肿瘤中的大多数TP53突变是错义取代，这导致全长突变蛋白的表达，这些蛋白在癌细胞中积累，并可能赋予独特的功能获得（GOF）活性以促进肿瘤发生事件。最近，突变p53蛋白已被证明介导代谢变化，作为一种新型GOF促进肿瘤发展。有一个强有力的理由，GOF活动，包括细胞代谢的改变，可能会有所不同的p53突变体之间。因此，不同突变型p53蛋白对癌细胞代谢的影响在很大程度上是未知的。在这项研究中，我们代谢分析了几个人经常发生的p53突变体在癌症中，重点是糖酵解和线粒体氧化磷酸化途径。我们的研究强调了不同p53突变体在其对代谢的影响方面的多样性，这可能为开发针对突变型p53变体的更有效的靶向药理学方法提供基础。
TP53 is one of the most commonly mutated genes in human cancers. Unlike other tumor suppressors that are frequently deleted or acquire loss-of-function mutations, the majority of TP53 mutations in tumors are missense substitutions, which lead to the expression of full-length mutant proteins that accumulate in cancer cells and may confer unique gain-of-function (GOF) activities to promote tumorigenic events. Recently, mutant p53 proteins have been shown to mediate metabolic changes as a novel GOF to promote tumor development. There is a strong rationale that the GOF activities, including alterations in cellular metabolism, might vary between the different p53 mutants. Accordingly, the effect of different mutant p53 proteins on cancer cell metabolism is largely unknown. In this study, we have metabolically profiled several individual frequently occurring p53 mutants in cancers, focusing on glycolytic and mitochondrial oxidative phosphorylation pathways. Our investigation highlights the diversity of different p53 mutants in terms of their effect on metabolism, which might provide a foundation for the development of more effective targeted pharmacological approaches toward variants of mutant p53.