p53 Represses the Mevalonate Pathway to Mediate Tumor Suppression.
ATP Binding Cassette Transporter 1
/ metabolism
Animals
Cell Line
Cholesterol
/ metabolism
Female
Genes, Tumor Suppressor
HCT116 Cells
Hepatocytes
/ metabolism
Humans
Liver
/ metabolism
Male
Mevalonic Acid
/ metabolism
Mice
Mice, Inbred C57BL
Neoplasms
/ genetics
Promoter Regions, Genetic
Sterol Regulatory Element Binding Protein 2
/ metabolism
Terpenes
/ metabolism
Tumor Suppressor Protein p53
/ metabolism
ABCA1
SREBP-2
cancer metabolism
mevalonate pathway
p53
tumor suppression
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
24 01 2019
24 01 2019
Historique:
received:
24
11
2017
revised:
24
08
2018
accepted:
09
11
2018
pubmed:
26
12
2018
medline:
27
11
2019
entrez:
25
12
2018
Statut:
ppublish
Résumé
There are still gaps in our understanding of the complex processes by which p53 suppresses tumorigenesis. Here we describe a novel role for p53 in suppressing the mevalonate pathway, which is responsible for biosynthesis of cholesterol and nonsterol isoprenoids. p53 blocks activation of SREBP-2, the master transcriptional regulator of this pathway, by transcriptionally inducing the ABCA1 cholesterol transporter gene. A mouse model of liver cancer reveals that downregulation of mevalonate pathway gene expression by p53 occurs in premalignant hepatocytes, when p53 is needed to actively suppress tumorigenesis. Furthermore, pharmacological or RNAi inhibition of the mevalonate pathway restricts the development of murine hepatocellular carcinomas driven by p53 loss. Like p53 loss, ablation of ABCA1 promotes murine liver tumorigenesis and is associated with increased SREBP-2 maturation. Our findings demonstrate that repression of the mevalonate pathway is a crucial component of p53-mediated liver tumor suppression and outline the mechanism by which this occurs.
Identifiants
pubmed: 30580964
pii: S0092-8674(18)31503-4
doi: 10.1016/j.cell.2018.11.011
pmc: PMC6483089
mid: NIHMS1010773
pii:
doi:
Substances chimiques
ATP Binding Cassette Transporter 1
0
Sterol Regulatory Element Binding Protein 2
0
TP53 protein, human
0
Terpenes
0
Tumor Suppressor Protein p53
0
Cholesterol
97C5T2UQ7J
Mevalonic Acid
S5UOB36OCZ
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
564-580.e19Subventions
Organisme : NIH HHS
ID : U54 OD020355
Pays : United States
Organisme : NCI NIH HHS
ID : F31 CA192835
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA087497
Pays : United States
Organisme : NCI NIH HHS
ID : F32 CA203146
Pays : United States
Informations de copyright
Copyright © 2018 Elsevier Inc. All rights reserved.
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