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 events2. 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 neighbours2,3. 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.

Mechanical cues control mutant p53 stability through a mevalonate-RhoA axis / Ingallina, Eleonora; Sorrentino, Giovanni; Bertolio, Rebecca; Lisek, Kamil; Zannini, Alessandro; Azzolin, Luca; Severino, Luisa Ulloa; Scaini, Denis; Mano, Miguel; Mantovani, Fiamma; Rosato, Antonio; Bicciato, Silvio; Piccolo, Stefano; Del Sal, Giannino. - In: NATURE CELL BIOLOGY. - ISSN 1465-7392. - 20:1(2018), pp. 28-35. [10.1038/s41556-017-0009-8]

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

Scaini, Denis;
2018-01-01

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 events2. 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 neighbours2,3. 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.
2018
20
1
28
35
http://www.nature.com/ncb/index.html
Ingallina, Eleonora; Sorrentino, Giovanni; Bertolio, Rebecca; Lisek, Kamil; Zannini, Alessandro; Azzolin, Luca; Severino, Luisa Ulloa; Scaini, Denis; Mano, Miguel; Mantovani, Fiamma; Rosato, Antonio; Bicciato, Silvio; Piccolo, Stefano; Del Sal, Giannino
File in questo prodotto:
File Dimensione Formato  
s41556-017-0009-8.pdf

non disponibili

Tipologia: Versione Editoriale (PDF)
Licenza: Non specificato
Dimensione 3.13 MB
Formato Adobe PDF
3.13 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11767/71301
Citazioni
  • ???jsp.display-item.citation.pmc??? 71
  • Scopus 98
  • ???jsp.display-item.citation.isi??? 95
social impact