Oncogenic beta-catenin is required for bone morphogenetic protein 4 expression in human cancer cells.
Somatic cell gene targeting was used to create an isogenic set of human colon cancer cells that differs only in the presence or absence of their endogenous activated beta-catenin oncogene. Affymetrix Genechip expression profiling of parental cells and gene-targeted derivatives identified numerous novel genes whose expression was dependent on the presence of oncogenic beta-catenin. The transforming growth factor-beta family member bone morphogenetic protein 4 (BMP4), whose receptor is mutated in a rare inherited gastrointestinal cancer predisposition syndrome, was the most highly differentially expressed gene. Additional experiments revealed that the oncogenic allele of beta-catenin specifically is absolutely required for BMP4 expression and secretion by human cancer cells and that BMP4 is overexpressed and secreted by human colon cancer cells with mutant adenomatous polyposis coli genes. These data identify the presence of regulatory interactions between the Wnt and BMP signaling pathways in cancer pathogenesis, providing an intriguing connection between the sporadic and inherited forms of a common human malignancy.
Kim
Jung-Sik
JS
Department of Oncology, Lombardi Cancer Center, Georgetown University School of Medicine, 3970 Reservoir Road NW, Washington, DC 20007, USA.
Crooks
Heather
H
Dracheva
Tatiana
T
Nishanian
Tagvor G
TG
Singh
Baljit
B
Jen
Jin
J
Waldman
Todd
T
D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1; D009154:Mutation; D009857:Oncogenes; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D051176:beta Catenin
C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin