Kinase-inactive glycogen synthase kinase 3beta promotes Wnt signaling and mammary tumorigenesis.
Cancer Res
; 65(13): 5792-801, 2005 Jul 01.
Article
em En
| MEDLINE
| ID: mdl-15994955
ABSTRACT
Recent studies have implicated ectopic activation of the Wnt pathway in many human cancers, including breast cancer. beta-catenin is a critical coactivator in this signaling pathway and is regulated in a complex fashion by phosphorylation, degradation, and nuclear translocation. Glycogen synthase kinase 3beta (GSK3beta) phosphorylation of the NH2-terminal domain of beta-catenin targets it for ubiquitination and proteosomal degradation. We hypothesized that expression of kinase-inactive GSK3beta (KI-GSK3beta) in mammary glands would function in a dominant-negative fashion by antagonizing the endogenous activity of GSK3beta and promoting breast cancer development. Consistent with this, we find that KI-GSK3beta stabilizes beta-catenin expression, catalyzes its localization to the nucleus, and up-regulates the downstream target gene, cyclin D1, in vitro. In vivo, transgenic mice overexpressing the KI-GSK3beta under the control of the mouse mammary tumor virus-long terminal repeat develop mammary tumors with overexpression of beta-catenin and cyclin D1. Thus, antagonism of GSK3beta activity is oncogenic in the mammary epithelium; mutation or pharmacologic down-regulation of GSK3beta could promote mammary tumors.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transformação Celular Neoplásica
/
Quinase 3 da Glicogênio Sintase
/
Peptídeos e Proteínas de Sinalização Intercelular
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Neoplasias Mamárias Experimentais
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Ano de publicação:
2005
Tipo de documento:
Article