Mechanical cues control mutant p53 stability through a mevalonate-RhoA axis

Eleonora Ingallina, Giovanni Sorrentino, Rebecca Bertolio, Kamil Lisek, Alessandro Zannini, Luca Azzolin, Luisa Ulloa Severino, Denis Scaini, Miguel Mano, Fiamma Mantovani, Antonio Rosato, Silvio Bicciato, Stefano Piccolo, Giannino Del Sal

Research output: Contribution to journalArticle

Abstract

Tumour-associated p53 missense mutants act as driver oncogenes affecting cancer progression, metastatic potential and drug resistance (gain-of-function) 1 . Mutant p53 protein stabilization is a prerequisite for gain-of-function manifestation; however, it does not represent an intrinsic property of p53 mutants, but rather requires secondary events 2 . Moreover, mutant p53 protein levels are often heterogeneous even within the same tumour, raising questions on the mechanisms that control local mutant p53 accumulation in some tumour cells but not in their neighbours 2,3 . By investigating the cellular pathways that induce protection of mutant p53 from ubiquitin-mediated proteolysis, we found that HDAC6/Hsp90-dependent mutant p53 accumulation is sustained by RhoA geranylgeranylation downstream of the mevalonate pathway, as well as by RhoA- and actin-dependent transduction of mechanical inputs, such as the stiffness of the extracellular environment. Our results provide evidence for an unpredicted layer of mutant p53 regulation that relies on metabolic and mechanical cues.

Original languageEnglish
Pages (from-to)28-35
Number of pages8
JournalNature Cell Biology
Volume20
Issue number1
DOIs
Publication statusPublished - Jan 2018

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