The interplay between mutant p53 and the mevalonate pathway

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Missense mutations in the TP53 gene lead to accumulation of dysfunctional TP53 proteins in tumors, showing oncogenic gain-of-function (GOF) activities. Stabilization of mutant TP53 (mutp53) is required for the GOF; however, the mechanisms by which mutp53 promotes cancer progression and how mutp53 stability is regulated are not completely understood. Recent work from our laboratory has identified statins, inhibitors of the mevalonate pathway, as degraders of conformational mutp53. Specific reduction of mevalonate-5-phosphate (MVP), a metabolic intermediate in the mevalonate pathway, by statins or mevalonate kinase (MVK) knockdown triggers CHIP ubiquitin ligase-mediated degradation of conformational mutp53 by inhibiting interaction between mutp53 and DNAJA1, a Hsp40 family member. Thus, the mevalonate pathway contributes to mutp53 stabilization. Given that mutp53 is shown to promote cancer progression by upregulating mRNA expression of mevalonate pathway enzymes by binding to the sterol regulatory element-binding protein 2 (SREBP2) and subsequently increasing activities of mevalonate pathway-associated oncogenic proteins (e.g., Ras, Rho, YAP/TAZ), there is a positive-feedback loop between mutp53 and the mevalonate pathway. Here, we summarize recent evidence linking the mevalonate pathway-mutp53 axis with cancer progression and further discuss the clinical relevance of this axis.

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We thank Atul Ranjan and Satomi Yamamoto for editing the manuscript and helpful discussion. This manuscript is supported by NIH R01 CA174735 (T.I.) grant.

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  1. Edited by G. Melino


  1. Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, 66160, USA

    • Alejandro Parrales
    • , Elizabeth Thoenen
    •  & Tomoo Iwakuma


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The authors declare that they have no competing interests.

Corresponding author

Correspondence to Tomoo Iwakuma.