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

doi:10.1038/s41556-017-0009-8

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^*

^*Corresponding author for this work

Cardiovascular Sciences

Research output: Contribution to journal › Article › peer-review

105 Citations (Scopus)

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 language	English
Pages (from-to)	28-35
Number of pages	8
Journal	Nature Cell Biology
Volume	20
Issue number	1
DOIs	https://doi.org/10.1038/s41556-017-0009-8
Publication status	Published - 1 Jan 2018

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41556-017-0009-8

Cite this

@article{2f704040fbb24cbdb21108483b3efafc,

title = "Mechanical cues control mutant p53 stability through a mevalonate-RhoA axis",

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. ",

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

note = "Funding Information: We thank A. Testa for discussions and proofreading the manuscript. We acknowledge G. Pastore for technical support. We thank S. Giulitti for preparation of hydrogels. We acknowledge support by the Italian Health Ministry (RF-2011-02346976 to G.D.S. and GR-2011-02348707 to D.S.), the Italian University and Research Ministry (PRIN-2015-8KZKE3), the Cariplo Foundation (grant no. 2014-0812) and Beneficentia-Stiftung to G.D.S. This work was supported by grants from the Associazione Italiana per la Ricerca sul Cancro (AIRC) and AIRC Special Program Molecular Clinical Oncology {\textquoteleft}5 per mille{\textquoteright} (grant no. 10016) to G.D.S., S.B., A.R. and S.P., and AIRC IG (grant no. 17659) to G.D.S. This project has received funding from the European Research Council (ERC) under the European Union{\textquoteright}s Horizon 2020 research and innovation programme (grant agreement no. 670126-DENOVOSTEM) and an AIRC PI-Grant and by Epigenetics Flagship project CNR-Miur grants to S.P. M.M. is supported by the FIRB RBAP11Z4Z9 project from the Italian Ministry of Education and the FCT Investigator Programme IF/00694/2013 from the Portuguese Foundation for Science and Technology (FCT), Portugal. R.B. is a fellow of the Fondazione Italiana per la Ricerca sul Cancro (FIRC). Publisher Copyright: {\textcopyright} The Authors 2017, under exclusive licence to Macmillan Publishers Ltd., part of Springer Nature.",

year = "2018",

month = jan,

day = "1",

doi = "10.1038/s41556-017-0009-8",

language = "English",

volume = "20",

pages = "28--35",

journal = "Nature Cell Biology",

issn = "1465-7392",

publisher = "Nature Research",

number = "1",

}

TY - JOUR

T1 - Mechanical cues control mutant p53 stability through a mevalonate-RhoA axis

AU - Ingallina, Eleonora

AU - Sorrentino, Giovanni

AU - Bertolio, Rebecca

AU - Lisek, Kamil

AU - Zannini, Alessandro

AU - Azzolin, Luca

AU - Severino, Luisa Ulloa

AU - Scaini, Denis

AU - Mano, Miguel

AU - Mantovani, Fiamma

AU - Rosato, Antonio

AU - Bicciato, Silvio

AU - Piccolo, Stefano

AU - Del Sal, Giannino

N1 - Funding Information: We thank A. Testa for discussions and proofreading the manuscript. We acknowledge G. Pastore for technical support. We thank S. Giulitti for preparation of hydrogels. We acknowledge support by the Italian Health Ministry (RF-2011-02346976 to G.D.S. and GR-2011-02348707 to D.S.), the Italian University and Research Ministry (PRIN-2015-8KZKE3), the Cariplo Foundation (grant no. 2014-0812) and Beneficentia-Stiftung to G.D.S. This work was supported by grants from the Associazione Italiana per la Ricerca sul Cancro (AIRC) and AIRC Special Program Molecular Clinical Oncology ‘5 per mille’ (grant no. 10016) to G.D.S., S.B., A.R. and S.P., and AIRC IG (grant no. 17659) to G.D.S. This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 670126-DENOVOSTEM) and an AIRC PI-Grant and by Epigenetics Flagship project CNR-Miur grants to S.P. M.M. is supported by the FIRB RBAP11Z4Z9 project from the Italian Ministry of Education and the FCT Investigator Programme IF/00694/2013 from the Portuguese Foundation for Science and Technology (FCT), Portugal. R.B. is a fellow of the Fondazione Italiana per la Ricerca sul Cancro (FIRC). Publisher Copyright: © The Authors 2017, under exclusive licence to Macmillan Publishers Ltd., part of Springer Nature.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85038410130&partnerID=8YFLogxK

U2 - 10.1038/s41556-017-0009-8

DO - 10.1038/s41556-017-0009-8

M3 - Article

C2 - 29255172

AN - SCOPUS:85038410130

SN - 1465-7392

VL - 20

SP - 28

EP - 35

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 1

ER -

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

Abstract

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this