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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
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The interplay between mutant p53 and the mevalonate pathway.
Alejandro Parrales1, Elizabeth Thoenen1, Tomoo Iwakuma2
1Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, 66160, USA.
Cell Death and Differentiation
|December 15, 2017
Summary
Statins degrade mutant TP53 (mutp53) by reducing mevalonate-5-phosphate, a key step in the mevalonate pathway. This finding reveals a positive feedback loop between mutp53 and the mevalonate pathway in cancer progression.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Missense mutations in the TP53 gene result in dysfunctional mutant TP53 (mutp53) proteins with oncogenic gain-of-function (GOF) activities.
- The mechanisms underlying mutp53's role in cancer progression and its stabilization are not fully understood.
- The mevalonate pathway is implicated in cancer, but its direct link to mutp53 stabilization and function requires further elucidation.
Purpose of the Study:
- To investigate the role of the mevalonate pathway in the stabilization of mutant TP53 (mutp53).
- To identify mechanisms by which mutp53 stability is regulated.
- To explore the therapeutic potential of targeting the mevalonate pathway in cancers with mutp53.
Main Methods:
- Utilized statins, known inhibitors of the mevalonate pathway, to assess their effect on mutp53 stability.
- Investigated the impact of reducing mevalonate-5-phosphate (MVP) levels via statins or mevalonate kinase (MVK) knockdown on mutp53 degradation.
- Examined the interaction between mutp53, DNAJA1, and the CHIP ubiquitin ligase in response to mevalonate pathway modulation.
- Analyzed the effect of mutp53 on the expression of mevalonate pathway enzymes and oncogenic proteins like Ras, Rho, and YAP/TAZ.
Main Results:
- Statins were identified as potent degraders of conformational mutant TP53 (mutp53).
- Reduction of mevalonate-5-phosphate (MVP) by statins or MVK knockdown promotes CHIP-mediated degradation of mutp53 by disrupting the mutp53-DNAJA1 interaction.
- A positive feedback loop exists where mutp53 upregulates mevalonate pathway enzymes via SREBP2, enhancing oncogenic protein activities.
Conclusions:
- The mevalonate pathway is crucial for stabilizing mutant TP53 (mutp53), contributing to its oncogenic gain-of-function.
- Targeting the mevalonate pathway, for example with statins, can induce degradation of mutp53.
- The interplay between the mevalonate pathway and mutp53 represents a significant axis in cancer progression with potential clinical relevance.
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