Department of Molecular Biology and Biochemistry; University of California, Irvine, Irvine, CA 92697, USA.
Center for Informatics, City of Hope National Medical Center, Duarte, CA 91010, USA; Department of Computational & Quantitative Medicine, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.
Cell Rep. 2019 Mar 12;26(11):3051-3060.e4. doi: 10.1016/j.celrep.2019.02.037.
Cancer cells heavily depend on the amino acid glutamine to meet the demands associated with growth and proliferation. Due to the rapid consumption of glutamine, cancer cells frequently undergo glutamine starvation in vivo. We and others have shown that p53 is a critical regulator in metabolic stress resistance. To better understand the molecular mechanisms by which p53 activation promotes cancer cell adaptation to glutamine deprivation, we identified p53-dependent genes that are induced upon glutamine deprivation by using RNA-seq analysis. We show that Slc7a3, an arginine transporter, is significantly induced by p53. We also show that increased intracellular arginine levels following glutamine deprivation are dependent on p53. The influx of arginine has minimal effects on known metabolic pathways upon glutamine deprivation. Instead, we found arginine serves as an effector for mTORC1 activation to promote cell growth in response to glutamine starvation. Therefore, we identify a p53-inducible gene that contributes to the metabolic stress response.
癌细胞严重依赖氨基酸谷氨酰胺来满足生长和增殖相关的需求。由于谷氨酰胺的快速消耗，癌细胞在体内经常经历谷氨酰胺饥饿。我们和其他人已经表明，p53 是代谢应激抵抗的关键调节因子。为了更好地理解 p53 激活促进癌细胞适应谷氨酰胺缺乏的分子机制，我们通过 RNA-seq 分析鉴定了谷氨酰胺缺乏时 p53 依赖性诱导的基因。我们发现 Slc7a3（一种精氨酸转运体）可被 p53 显著诱导。我们还发现，谷氨酰胺缺乏后细胞内精氨酸水平的增加依赖于 p53。谷氨酰胺缺乏后，精氨酸的流入对已知的代谢途径几乎没有影响。相反，我们发现精氨酸作为 mTORC1 激活的效应物，以促进细胞生长来响应谷氨酰胺饥饿。因此，我们鉴定了一个 p53 诱导的基因，它有助于代谢应激反应。
