Activation of the Wnt pathway interferes with serum response element-driven transcription of immediate early genes.
Mutational activation of the Wnt signaling pathway is a common early event in colorectal tumorigenesis, and the identification of target genes regulated by this pathway will provide a better understanding of tumor progression. Gene expression profiling on oligonucleotide microarrays revealed reduced expression of the immediate early genes fos and fosB following stimulation of cells by Wnt-1. Further analysis demonstrated that serum or 12-O-tetradecanoylphorbol-13-acetate activation of several immediate early genes including fos, fosB, junB, and egr1 was inhibited by Wnt signaling. Wnt signaling inhibited transcriptional activation driven by the serum response element without altering the activation of the extracellular signal-regulated kinase cascade or ternary complex formation at the fos serum response element promoter. The Wnt-mediated repression of c-Fos, FosB, and JunB expression was consistent with a decrease in their binding to an AP-1 promoter element and decreased target gene transcription. The expression of fos, fosB, junB, and egr1 was also repressed in human colon tumors relative to patient matched normal tissue. By contrast, the fos family member fra-1 was up-regulated in the human colon tumors, suggesting a compensatory mechanism for the reduction in fos and fosB expression. The results indicate that Wnt signaling can repress the expression of certain immediate early genes, and that this effect is consistent with changes in gene expression observed in human colorectal tumors.
Tice
David A
DA
Department of Molecular Oncology, Genentech, Inc., South San Francisco, California 94080, USA.
Soloviev
Irina
I
Polakis
Paul
P
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D003110:Colonic Neoplasms; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000187:drug effects; D051766:Early Growth Response Protein 1; D005786:Gene Expression Regulation; D017781:Genes, Immediate-Early; D017930:Genes, Reporter; D016762:Genes, fos / Q000187:drug effects; D016758:Genes, jun / Q000187:drug effects; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics; D008156:Luciferases / Q000235:genetics; D051379:Mice; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins; D051155:Wnt1 Protein; D029961:Zebrafish Proteins
D017931:DNA Primers; D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D017874:Immediate-Early Proteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; C495247:WNT1 protein, human; D051153:Wnt Proteins; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D029961:Zebrafish Proteins; D000255:Adenosine Triphosphate; D008156:Luciferases; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D011505:Protein-Tyrosine Kinases; D013755:Tetradecanoylphorbol Acetate