Regulation of alpha-fetoprotein gene expression by antagonism between AP-1 and the glucocorticoid receptor at their overlapping binding site.
We show here that the alpha-fetoprotein gene (AFP) promoter can be regulated by AP-1 activity using transient transfection assays. AFP promoter activity induced by c-jun/c-fos can be repressed by cotransfected glucocorticoid receptor. The DNA sequence conferring AP-1 activity was located in the proximal promoter region. Gel retardation assays using the AFP proximal promoter identified an AP-1-like sequence which can bind to bacterially expressed c-jun protein. This AP-1-like element, when cloned into the tk promoter, responds to the AP-1 activity of c-jun/c-fos products in both CV-1 and F-9 cells. The element overlaps with a consensus glucocorticoid-responsive element which was shown to confer negative modulation of AFP promoter activity. A 23-base pair DNA element containing the overlapping glucocorticoid-responsive element and AP-1 sites can be positively regulated by glucocorticoid receptor in the absence of c-jun/c-fos products. When plasmids expressing glucocorticoid receptor, c-jun and c-fos are cotransfected together, they repress each other. Thus, these data demonstrate that negative regulation of the AFP gene by glucocorticoid may be due to the interference of AP-1 activity by glucocorticoid receptor either by direct competition for DNA binding or via protein-protein interaction. They provide another example of transcriptional regulation of developing-associated genes between two major signal transduction pathways in response to extracellular stimuli. This supports the model that expression of alpha-fetoprotein is regulated during development by the effect on transcription of antagonism between glucocorticoid receptor and fos/jun.
Zhang
X K
XK
Department of Biochemistry, University of Vermont, College of Medicine, Burlington 05405.
Dong
J M
JM
Chiu
J F
JF
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D005786:Gene Expression Regulation; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D000509:alpha-Fetoproteins / Q000235:genetics*
D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors; D000509:alpha-Fetoproteins; D003907:Dexamethasone