Eriksson Matilda, Ambroise Gorbatchev, Ouchida Amanda Tomie, Lima Queiroz Andre, Smith Dominique, Gimenez-Cassina Alfredo, Iwanicki Marcin P, Muller Patricia A, Norberg Erik, Vakifahmetoglu-Norberg Helin
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Mol Cell Biol. 2017 Nov 28;37(24). doi: 10.1128/MCB.00328-17. Print 2017 Dec 15.
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 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.
是人类癌症中最常发生突变的基因之一。与其他经常被删除或获得功能丧失突变的肿瘤抑制基因不同，肿瘤中的大多数突变是错义替换，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）活性以促进致瘤事件。最近，突变型p53蛋白已被证明作为一种新的功能获得机制介导代谢变化以促进肿瘤发展。有充分的理由认为，包括细胞代谢改变在内的功能获得活性可能在不同的p53突变体之间有所不同。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尚不清楚。在本研究中，我们对癌症中几种常见的p53突变体进行了代谢分析，重点关注糖酵解和线粒体氧化磷酸化途径。我们的研究突出了不同p53突变体在代谢影响方面的多样性，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。
