Kinase-inactive glycogen synthase kinase 3β promotes Wnt signaling and mammary tumorigenesis

Marganit Farago, Isabel Dominguez, Esther Landesman-Bollag, Xin Xu, Andrea Rosner, Robert Cardiff, David C. Seldin

Research output: Contribution to journalArticle

109 Scopus citations

Abstract

Recent studies have implicated ectopic activation of the Wnt pathway in many human cancers, including breast cancer, β-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 3β (GSK3β) phosphorylation of the NH2-terminal domain of β-catenin targets it for ubiquitination and proteosomal degradation. We hypothesized that expression of kinase-inactive GSK3β (KI-GSK3β) in mammary glands would function in a dominant-negative fashion by antagonizing the endogenous activity of GSK3β and promoting breast cancer development. Consistent with this, we find that KI-GSK3β stabilizes β-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-GSK3β under the control of the mouse mammary tumor virus-long terminal repeat develop mammary tumors with overexpression of β-catenin and cyclin D1. Thus, antagonism of GSK3β activity is oncogenic in the mammary epithelium; mutation or pharmacologic down-regulation of GSK3β could promote mammary tumors.

Original languageEnglish (US)
Pages (from-to)5792-5801
Number of pages10
JournalCancer Research
Volume65
Issue number13
DOIs
StatePublished - Jul 1 2005

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Farago, M., Dominguez, I., Landesman-Bollag, E., Xu, X., Rosner, A., Cardiff, R., & Seldin, D. C. (2005). Kinase-inactive glycogen synthase kinase 3β promotes Wnt signaling and mammary tumorigenesis. Cancer Research, 65(13), 5792-5801. https://doi.org/10.1158/0008-5472.CAN-05-1021