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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cell Nucleus / metabolism
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism*
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Cyclin D
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Cyclins / biosynthesis
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Cytoskeletal Proteins / biosynthesis
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Cytoskeletal Proteins / genetics
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Enzyme Activation
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Female
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Glycogen Synthase Kinase 3 / antagonists & inhibitors*
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Glycogen Synthase Kinase 3 / genetics
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Humans
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Intercellular Signaling Peptides and Proteins / physiology*
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Mammary Neoplasms, Experimental / enzymology*
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Mammary Neoplasms, Experimental / genetics
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Mammary Neoplasms, Experimental / metabolism
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Mammary Neoplasms, Experimental / pathology
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Mice
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Mice, Transgenic
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RNA, Small Interfering / genetics
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Signal Transduction
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Trans-Activators / biosynthesis
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Trans-Activators / genetics
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Transfection
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Up-Regulation
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Wnt Proteins
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beta Catenin
Substances
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CTNNB1 protein, human
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CTNNB1 protein, mouse
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Cyclin D
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Cyclins
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Cytoskeletal Proteins
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Intercellular Signaling Peptides and Proteins
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RNA, Small Interfering
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Trans-Activators
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Wnt Proteins
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beta Catenin
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, mouse
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Glycogen Synthase Kinase 3