Regulation of Cyclooxygenase-2 and Periostin by Wnt-3 in Mouse Mammary Epithelial Cells*

Wnt family members are critical in developmental processes and have been shown to promote carcinogenesis when ectopically expressed in the mouse mammary gland. The gene expression pattern mediated by Wnt is pivotal for these diverse responses. The Wnt pathway has been conserved among different species. Genetic studies have shown that Wnt effects are mediated, at least in part, by β-catenin, which regulates transcription of “downstream genes.” Wnt stimulation inactivates glycogen-synthase kinase-3β (GSK-3) with subsequent stabilization of β-catenin, which after heterodimerizing with lymphocyte enhancer factor-1/T-cell factor cofactors stimulates transcription. To establish whether Wnt-stimulated transcription is mediated solely by β-catenin, a comparison was made of gene expression profiles in response to Wnt-3, overexpression of β-catenin, and inhibition of GSK-3. Infection of cells with Wnt-3 and inhibition of GSK-3 regulate a set of genes that include cyclooxygenase-2 and periostin. Interestingly, overexpression of β-catenin or reducing β-catenin levels with antisense oligonucleotide transfection did not have any effect on cyclooxygenase-2 or periostin expression, thereby defining a Wnt pathway, which cannot be mimicked by β-catenin overexpression.

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