Mechanical cues control mutant p53 stability through a mevalonate-RhoA axis.
Nat Cell Biol
; 20(1): 28-35, 2018 01.
Article
en En
| MEDLINE
| ID: mdl-29255172
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Neoplasias de la Mama
/
Regulación Neoplásica de la Expresión Génica
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Proteína p53 Supresora de Tumor
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Proteína de Unión al GTP rhoA
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Mecanotransducción Celular
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Ácido Mevalónico
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Nat Cell Biol
Año:
2018
Tipo del documento:
Article
País de afiliación:
Italia
Pais de publicación:
Reino Unido