p53 regulation of ammonia metabolism through urea cycle controls polyamine biosynthesis

• Published in: Nature (London) Vol. 567; no. 7747; pp. 253 - 256
• Main Authors: Li, Le, Mao, Youxiang, Zhao, Lina, Li, Lijia, Wu, Jinjun, Zhao, Mengjia, Du, Wenjing, Yu, Li, Jiang, Peng
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2019; Nature Publishing Group
• Subjects: Accumulation; Ammonia; Autophagy; Biosynthesis; Breast cancer; Cancer; Cancer cells; Cell adhesion & migration; Cell cycle; Cell growth; Cell proliferation; Dehydrogenases; Enzyme inhibitors; Enzymes; Gene expression; Gene mutation; Genes; Genetic engineering; Humanities and Social Sciences; Kinases; Letter; MDM2 protein; Messenger RNA; Metabolism; multidisciplinary; Mutation; Nonprescription drugs; p53 Protein; Physiological aspects; Physiological regulation; Physiological research; Polyamines; Proteins; RNA; Science; Science (multidisciplinary); Tetracyclines; Transcription; Transcription (Genetics); Translation (Genetics); Tumor proteins; Tumors; Urea; Ureas
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-019-0996-7

Cancer cells exhibit altered and usually increased metabolic processes to meet their high biogenetic demands 1 , 2 . Under these conditions, ammonia is concomitantly produced by the increased metabolic processing. However, it is unclear how tumour cells dispose of excess ammonia and what outcomes might be caused by the accumulation of ammonia. Here we report that the tumour suppressor p53, the most frequently mutated gene in human tumours, regulates ammonia metabolism by repressing the urea cycle. Through transcriptional downregulation of CPS1 , OTC and ARG1 , p53 suppresses ureagenesis and elimination of ammonia in vitro and in vivo, leading to the inhibition of tumour growth. Conversely, downregulation of these genes reciprocally activates p53 by MDM2-mediated mechanism(s). Furthermore, the accumulation of ammonia causes a significant decline in mRNA translation of the polyamine biosynthetic rate-limiting enzyme ODC, thereby inhibiting the biosynthesis of polyamine and cell proliferation. Together, these findings link p53 to ureagenesis and ammonia metabolism, and further reveal a role for ammonia in controlling polyamine biosynthesis and cell proliferation. p53 regulates the metabolism of ammonia by repressing genes of the urea cycle that function to eliminate excess ammonia.