Restoring p53 function in human melanoma cells by inhibiting MDM2 and cyclin B1/CDK1-phosphorylated nuclear iASPP.
Cancer Cell
; 23(5): 618-33, 2013 May 13.
Article
em En
| MEDLINE
| ID: mdl-23623661
ABSTRACT
Nearly 90% of human melanomas contain inactivated wild-type p53, the underlying mechanisms for which are not fully understood. Here, we identify that cyclin B1/CDK1-phosphorylates iASPP, which leads to the inhibition of iASPP dimerization, promotion of iASPP monomer nuclear entry, and exposure of its p53 binding sites, leading to increased p53 inhibition. Nuclear iASPP is enriched in melanoma metastasis and associates with poor patient survival. Most wild-type p53-expressing melanoma cell lines coexpress high levels of phosphorylated nuclear iASPP, MDM2, and cyclin B1. Inhibition of MDM2 and iASPP phosphorylation with small molecules induced p53-dependent apoptosis and growth suppression. Concurrent p53 reactivation and BRAFV600E inhibition achieved additive suppression in vivo, presenting an alternative for melanoma therapy.
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
6_ODS3_enfermedades_notrasmisibles
Base de dados:
MEDLINE
Assunto principal:
Proteínas Repressoras
/
Proteína Quinase CDC2
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Proteína Supressora de Tumor p53
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Peptídeos e Proteínas de Sinalização Intracelular
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Ciclina B1
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Melanoma
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Cancer Cell
Ano de publicação:
2013
Tipo de documento:
Article