Activator protein 2alpha associates with adenomatous polyposis coli/beta-catenin and Inhibits beta-catenin/T-cell factor transcriptional activity in colorectal cancer cells.
In most human colorectal cancers, mutations in the adenomatous polyposis coli gene (APC) or CTNNB1 constitutively activate the beta-catenin/T-cell factor (TCF)/lymphoid enhancer factor (LEF) signaling pathway. Here, we show that the transcription factor activator protein (AP)-2alpha inhibited a beta-catenin/TCF-responsive reporter in human embryonic kidney 293 cells and in two human colorectal cancer lines, despite the fact that beta-catenin and TCF-4 protein levels were unchanged in the nucleus. Co-immunoprecipitation studies revealed that AP-2alpha formed a complex with APC and beta-catenin and that AP-2alpha disrupted beta-catenin/TCF-4 interactions in the nucleus. Thus, AP-2alpha.APC.beta-catenin complex formation appears to suppress beta-catenin transactivation by shifting the pool of nuclear beta-catenin toward an inactive form, having reduced binding to TCF/LEF transcription factors. Glutathione S-transferase pull-down assays showed that AP-2alpha physically associated with APC rather than with beta-catenin, and the AP-2alpha binding site was identified in the N terminus of APC, involving both the heptad and armadillo repeat domains, whereas the APC binding site in AP-2alpha was in the basic region of the C-terminal DNA binding domain. These findings provide the first evidence for a specific interaction between the tumor suppressor protein APC and the transcription factor AP-2alpha, and they suggest a link between the Wnt signaling pathway and various other pathways of development and differentiation associated with AP-2alpha.
Linus Pauling Institute and Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon 97331-6512, USA.
Qingjie
Q
Li
Roderick H
RH
Dashwood
D003598:Cytoskeletal Proteins / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000032:analysis / Q000502:physiology*; D017491:Genes, APC / Q000502:physiology*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D015398:Signal Transduction; D051820:TCF Transcription Factors; D015534:Trans-Activators / Q000502:physiology*; D058118:Transcription Factor 7-Like 2 Protein; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000032:analysis / Q000502:physiology*; D014158:Transcription, Genetic; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; C493673:TFAP2A protein, human; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D050656:Transcription Factor AP-2; D014157:Transcription Factors; D051176:beta Catenin