The orphan nuclear receptors COUP-TFI and COUP-TFII regulate expression of the gonadotropin LHβ gene.
Normal sexual development and reproductive function depend on precise temporal and quantitative expression of the pituitary gonadotropins, LH and FSH. LHβ-subunit gene expression is achieved by transcription factors acting at highly conserved and closely spaced cis-elements in the proximal 200 base pairs of the promoter. We now demonstrate that LHβ promoter activity is further regulated by the orphan nuclear receptors, chicken ovalbumin upstream promoter-transcription factors (COUP-TFI and COUP-TFII). These data establish that COUP-TFs are expressed in primary pituitary gonadotropes and two gonadotrope-derived cell lines. COUP-TFs bind to two promoter regions in the LHβ gene which overlap but are distinct from two previously defined cis-elements for another orphan nuclear receptor, steroidogenic factor-1 (SF-1). Transient transfection studies demonstrated that COUP-TFs stimulate LHβ gene promoter activity in the absence of SF-1, but blunt SF-1-mediated stimulation of gene expression in a reporter construct containing both SF-1 cis-elements (GSEs). Evaluation of constructs containing mutations or truncations in the GSEs revealed a complex pattern of activation and inhibition by COUP-TF on this promoter, suggesting multiple mechanisms by which this factor modulates LHβ gene expression. To our knowledge, these data are the first to demonstrate COUP-TF expression and function in pituitary gonadotropes.
Zheng
Weiming
W
Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9032, USA.
Horton
Cheryl D
CD
Kim
Jonathan
J
Halvorson
Lisa M
LM
D000818:Animals; D001483:Base Sequence; D001667:Binding, Competitive; D051838:COUP Transcription Factor I / Q000378:metabolism*; D051837:COUP Transcription Factor II / Q000378:metabolism*; D002460:Cell Line; D002645:Chickens; D047369:Chromatin Immunoprecipitation; D004247:DNA / Q000378:metabolism; D005786:Gene Expression Regulation; D052681:Gonadotrophs / Q000378:metabolism; D006801:Humans; D037101:Luteinizing Hormone, beta Subunit / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D011966:Receptors, LHRH / Q000235:genetics; D054339:Steroidogenic Factor 1 / Q000378:metabolism
D051838:COUP Transcription Factor I; D051837:COUP Transcription Factor II; D037101:Luteinizing Hormone, beta Subunit; D021122:Protein Subunits; D034741:RNA, Small Interfering; D011966:Receptors, LHRH; D054339:Steroidogenic Factor 1; D004247:DNA