Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
Cell Cycle. 2010 May;9(9):1706-10. doi: 10.4161/cc.9.9.11473. Epub 2010 May 10.
The p53 protein functions to prevent tumor development by restricting proliferation, motility and survival of abnormal or stressed cells. In addition to well-established roles, recent discoveries indicate a role for p53 in the regulation of pathways involved in energy metabolism. The metabolic functions of p53 can inhibit the shift to glycolysis that is characteristically seen in cancer cells, while favoring the energy production by mitochondrial oxidative phosphorylation. Identification of guanidinoacetate methyltransferase (GAMT) as a new p53 target connects p53 to creatine metabolism critical in the regulation of ATP homeostasis. The involvement of GAMT in both genotoxic and metabolic stressinduced apoptosis, as well as the requirement of p53-dependent upregulation of GAMT in glucose starvation-mediated fatty acid oxidation (FAO), demonstrate a further role of p53 in coordinating stress response with changes in cellular metabolism. Such activities of p53 would help to bring a better understanding of how cancer cells acquire unique metabolic features to maintain their own survival and proliferation, and might provide interesting clues toward the development of novel therapies.
p53 蛋白通过限制异常或应激细胞的增殖、运动和存活来发挥预防肿瘤发展的作用。除了已确立的作用外,最近的发现表明 p53 在调节能量代谢途径中发挥作用。p53 的代谢功能可以抑制通常在癌细胞中观察到的糖酵解转变,而有利于通过线粒体氧化磷酸化产生能量。胍基乙酸甲基转移酶 (GAMT) 被鉴定为 p53 的新靶标,将 p53 与肌酸代谢联系起来,肌酸代谢在调节 ATP 稳态中至关重要。GAMT 参与基因毒性和代谢应激诱导的细胞凋亡,以及 p53 依赖性上调在葡萄糖饥饿介导的脂肪酸氧化 (FAO) 中的作用,表明 p53 在协调应激反应与细胞代谢变化方面具有进一步的作用。p53 的这些活性有助于更好地理解癌细胞如何获得独特的代谢特征来维持自身的存活和增殖,并可能为开发新的治疗方法提供有趣的线索。