The cAMP response elements of the alpha subunit gene bind similar proteins in trophoblasts and gonadotropes but have distinct functional sequence requirements.
The alpha subunit gene encodes a common subunit shared by all glycoprotein hormones. This single copy gene is expressed in pituitary gonadotropes and thyrotropes of all mammals and in placental trophoblasts of primates and horses. Tandem cAMP response elements (CREs) in the promoter of the human gene are key mediators of this pattern of cell-specific expression. Replacing the palindromic CREs with non-primate variant CREs significantly attenuated activity in trophoblasts but not in gonadotropes. Furthermore, proteins binding the palindromic CRE cross-reacted with antibodies for CREB, CREM, ATF1, ATF2, and c-Jun, while proteins binding the variant CRE cross-reacted only with ATF2 and c-Jun antibodies. The data suggest that ATF2 and c-Jun can activate transcription through the CREs in gonadotropes but not in trophoblasts. Additional analyses indicated that while promoters with either palindromic or variant CREs have similar overall activity in gonadotropes, the variant CREs make a much smaller contribution to promoter activity than their palindromic counterparts. The weaker contribution of the variant CREs is compensated by the activity of two upstream elements present in the promoter. This compensation probably occurs through an indirect mechanism, as the binding affinity of proteins to the CRE is not influenced by the presence of these upstream elements.
Heckert
L L
LL
Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA. jhn@po.cwru.edu
Schultz
K
K
Nilson
J H
JH
D051697:Activating Transcription Factor 1; D051698:Activating Transcription Factor 2; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004268:DNA-Binding Proteins; D004591:Electrophoresis, Polyacrylamide Gel; D015292:Glycoprotein Hormones, alpha Subunit / Q000235:genetics*; D006066:Gonads / Q000378:metabolism*; D006801:Humans; D016350:Leucine Zippers; D016297:Mutagenesis, Site-Directed; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014327:Trophoblasts / Q000378:metabolism*
C497105:ATF2 protein, human; D051697:Activating Transcription Factor 1; D051698:Activating Transcription Factor 2; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D015292:Glycoprotein Hormones, alpha Subunit; D016755:Proto-Oncogene Proteins c-jun; D014157:Transcription Factors