p53 Represses the Mevalonate Pathway to Mediate Tumor Suppression

Moon, S. H., Huang, C. H., Houlihan, S. L., Regunath, K., Freed-Pastor, W. A., Morris, J. P. th, Tschaharganeh, D. F., Kastenhuber, E. R., Barsotti, A. M., Culp-Hill, R., Xue, W., Ho, Y. J., Baslan, T., Li, X., Mayle, A., de Stanchina, E., Zender, L., Tong, D. R., D'Alessandro, A., Lowe, S. W., Prives, C. (December 2018) p53 Represses the Mevalonate Pathway to Mediate Tumor Suppression. Cell, 176 (3). pp. 564-580. ISSN 0092-8674

URL: https://www.ncbi.nlm.nih.gov/pubmed/30580964
DOI: 10.1016/j.cell.2018.11.011

Abstract

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.

Item Type: Paper
Subjects: diseases & disorders > cancer > cancer types > liver cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p53
CSHL Authors:
Communities: CSHL labs > Lowe lab
Depositing User: Matthew Dunn
Date: 14 December 2018
Date Deposited: 04 Jan 2019 14:23
Last Modified: 04 Feb 2019 20:43
Related URLs:
URI: http://repository.cshl.edu/id/eprint/37524

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