pVHL suppresses kinase activity of Akt in a proline-hydroxylation-dependent manner.
Science
; 353(6302): 929-32, 2016 08 26.
Article
em En
| MEDLINE
| ID: mdl-27563096
ABSTRACT
Activation of the serine-threonine kinase Akt promotes the survival and proliferation of various cancers. Hypoxia promotes the resistance of tumor cells to specific therapies. We therefore explored a possible link between hypoxia and Akt activity. We found that Akt was prolyl-hydroxylated by the oxygen-dependent hydroxylase EglN1. The von Hippel-Lindau protein (pVHL) bound directly to hydroxylated Akt and inhibited Akt activity. In cells lacking oxygen or functional pVHL, Akt was activated to promote cell survival and tumorigenesis. We also identified cancer-associated Akt mutations that impair Akt hydroxylation and subsequent recognition by pVHL, thus leading to Akt hyperactivation. Our results show that microenvironmental changes, such as hypoxia, can affect tumor behaviors by altering Akt activation, which has a critical role in tumor growth and therapeutic resistance.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Prolina
/
Proteína Supressora de Tumor Von Hippel-Lindau
/
Proteínas Proto-Oncogênicas c-akt
/
Hipóxia Tumoral
/
Neoplasias
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Science
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Estados Unidos