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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
PubMed

Insights

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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