Kinase-inactive glycogen synthase kinase 3beta promotes Wnt signaling and mammary tumorigenesis.
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.
Molecular Medicine Program, Department of Medicine, Boston University Medical Center, Boston, Massachusetts, USA.
Marganit
M
Farago
Isabel
I
Dominguez
Esther
E
Landesman-Bollag
Xin
X
Xu
Andrea
A
Rosner
Robert D
RD
Cardiff
David C
DC
Seldin
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D056741:Cyclin D; D016213:Cyclins / Q000096:biosynthesis; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000235:genetics; D004789:Enzyme Activation; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics; D014162:Transfection; D015854:Up-Regulation; D051153:Wnt Proteins; D051176:beta Catenin
C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D056741:Cyclin D; D016213:Cyclins; D003598:Cytoskeletal Proteins; D036341:Intercellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D015534:Trans-Activators; D051153:Wnt Proteins; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3