Autocrine BMP4 signalling regulates ID3 proto-oncogene expression in human ovarian cancer cells.
Bone morphogenetic protein (BMP)-4 signalling leads to the direct upregulation of ID3 proto-oncogene expression in human ovarian cancer cells. An upstream BMP4-responsive enhancer element consisting of a palindromic BMP response element (BRE) site and CAGA box was identified ~3.0 kb upstream of the human ID3 gene, and a nearly-identical element exists in the second intron of the ID3 gene. BMP4 stimulation leads to the direct binding of Smads 1/5 and Smad4 to the upstream and intronic enhancers, and together both enhancers cooperate to yield heightened BMP4-mediated ID3 promoter activity. We further demonstrate that ID3 is overexpressed in human ovarian cancer cells when compared to normal ovarian surface epithelial cells, and treatment of ovarian cancer cells with the BMP4 antagonist Noggin abrogates endogenous ID3 gene expression. Our findings define the mechanism of BMP4-mediated ID3 gene expression, and support the notion that ovarian cancer cells possess autocrine BMP4 signalling required to sustain ID3 overexpression which may contribute to human ovarian cancer pathogenesis.
Shepherd
Trevor G
TG
Department of Pharmacology, Dalhousie University, Halifax, NS, Canada. tshephe6@uwo.ca
Thériault
Brigitte L
BL
Nachtigal
Mark W
MW
D000818:Animals; D019898:Autocrine Communication; D001483:Base Sequence; D015152:Blotting, Northern; D015153:Blotting, Western; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D004742:Enhancer Elements, Genetic; D005260:Female; D006801:Humans; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics* / Q000378:metabolism; D008156:Luciferases; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010053:Ovary / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D000090063:Proto-Oncogene Mas; D020218:Response Elements; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection
C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D051796:Inhibitor of Differentiation Proteins; C000715470:MAS1 protein, human; D009363:Neoplasm Proteins; D000090063:Proto-Oncogene Mas; C075640:ID3 protein, human; D008156:Luciferases