p53 regulation of ammonia metabolism through urea cycle controls polyamine biosynthesis
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 mi...
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Published in | Nature (London) Vol. 567; no. 7747; pp. 253 - 256 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group UK
01.03.2019
Nature Publishing Group |
Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0028-0836 1476-4687 |
DOI: | 10.1038/s41586-019-0996-7 |