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| Status |
Public on Oct 23, 2018 |
| Title |
p53 Represses the Mevalonate Pathway to Mediate Tumor Suppression |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
We have discovered that loss of wild-type p53 correlates with elevated expression of mevalonate pathway genes in murine liver cancer and in human tumors. Mechanistically p53 blocks activation of SREBP-2, the master transcriptional regulator of this pathway, by transcriptionally inducing the ABCA1 cholesterol transporter gene, which inhibits SREBP-2 maturation. In mice the increase in mevalonate gene expression occurs in premalignant p53-null hepatocytes at a stage when p53 is needed to actively suppress tumorigenesis. Either RNAi mediated suppression of key genes in the mevalonate pathway or pharmacological inhibition of its rate-limiting enzyme restricts the development of mouse hepatocellular carcinomas driven by p53 loss. Conversely, like p53 loss, ablation of ABCA1 promotes tumorigenesis in a murine model and is associated with increased SREBP-2 maturation. Our findings thereby demonstrate that repression of the mevalonate pathway is a crucial component of p53-mediated tumor suppression and outline the mechanism by which this occurs.
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| Overall design |
4 samples were analyzed in replicates of 2 conditions. 1. Control, p53 WT hepatocytes transduced with MYC transposons delivered by hydrodynamic tail vein injection and isolated 6 days after injection. 2. Experimental, p53 null hepatocytes transduced with MYC transposons delivered by hydrodynamic tail vein injection and isolated 6 days after injection.
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| Contributor(s) |
Prives C, Lowe SW, Moon S, Huang C, Houlihan SL |
| Citation(s) |
30580964 |
| |
| Submission date |
Oct 22, 2018 |
| Last update date |
Mar 21, 2019 |
| Contact name |
Yu-Jui Ho |
| E-mail(s) |
hoy@mskcc.org
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| Organization name |
Memorial Sloan Kettering Cancer Center
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| Department |
Cancer Biology & Genetics Program
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| Street address |
417 E 68th St
|
| City |
New York |
| State/province |
New York |
| ZIP/Postal code |
10065 |
| Country |
USA |
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| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
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| Samples (7)
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| Relations |
| BioProject |
PRJNA497787 |
| SRA |
SRP166270 |
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