Transcriptional regulation of the carcinoembryonic antigen gene. Identification of regulatory elements and multiple nuclear factors.
Human carcinoembryonic antigen (CEA) belongs to a family of membrane glycoproteins that are overexpressed in many carcinomas; CEA functions in vitro as a homotypic intercellular adhesion molecule and can inhibit differentiation when expressed ectopically in myoblasts. The regulation of expression of CEA is therefore of considerable interest. The CEA gene promoter region between -403 and -124 base pairs upstream of the translation initiation site directed high levels of expression in CEA-expression SW403 cells and was 3 times more active in differentiated than in undifferentiated Caco-2 cells, correlating exactly with the 3-fold increase in CEA mRNA seen in differentiated Caco-2 cells. Inclusion of additional upstream sequences between -1098 and -403 base pairs repressed all activity. By in vitro footprinting and deletion analyses, four cis-acting elements were mapped within the positive regulatory region, and one element within the silencing region. Several nuclear factors binding to these domains were identified: USF, Sp1, and an Sp1-like factor. By co-transfection, USF directly activated the CEA gene promoter in vivo in both SW403 and Caco-2 cells. In addition, the levels of factors binding to each positively acting element increased dramatically with differentiation in Caco-2 cells. Thus the transcriptional control of the CEA gene depends on the interaction of several regulatory elements that bind multiple specific factors.
Hauck
W
W
Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
Stanners
C P
CP
D001483:Base Sequence; D002272:Carcinoembryonic Antigen / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D004247:DNA; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D006801:Humans; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012045:Regulatory Sequences, Nucleic Acid; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D051720:Upstream Stimulatory Factors
D002272:Carcinoembryonic Antigen; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; C497181:USF1 protein, human; D051720:Upstream Stimulatory Factors; D004247:DNA