AR suppresses transcription of the LHbeta subunit by interacting with steroidogenic factor-1

Mol Endocrinol. 2001 Sep;15(9):1505-16. doi: 10.1210/mend.15.9.0691.

Abstract

Synthesis of LH is suppressed by feedback from gonadal steroids. Previously, we demonstrated that 779 bp of the bovine LHbeta promoter was sufficient to target expression of a chloramphenicol acetyltransferase reporter gene specifically to the pituitary in transgenic mice, and found that it was appropriately suppressed after administration of T or E2. In this study, we report that ligand-bound AR, but not ligand-bound ER, directly suppressed activity of the bovine LHbeta promoter when examined in a gonadotrope-derived cell line. Additional studies with mutated bovine LHbeta promoter constructs focused on the proximal 5'-flanking region because of the presence of several cis-acting elements that are highly conserved across all mammals. These include regulatory elements that bind steroidogenic factor 1 (SF-1), Egr-1, and Pitx1. When tested by cotransfection with AR, overexpression of Egr-1, Pitx1, and constitutively active steroidogenic factor 1 (SF-1DeltaLBD) each individually rescued androgen-mediated suppression of the bovine LHbeta promoter. This suggested a functional interaction between each of these transcription proteins and AR. In contrast, overexpression of full-length SF-1 was incapable of relieving the bovine LHbeta promoter from the suppressive effect imposed by AR. This suggested that the ligand-binding domain of SF-1 plays an important role in functional interactions that occur between this protein and AR. This notion was further supported by binding assays performed with glutathione-S-transferase-AR: these identified SF-1 as a key interactive partner and localized this interaction to the ligand-binding domain of the protein. Additional binding studies indicated that protein interactions between SF-1, Pitx1, and Egr-1 interfere with formation of a binary complex that contains AR and SF-1. Thus, we conclude that AR suppresses activity of the bovine LHbeta promoter through protein-protein interactions with SF-1 and that the degree of this interaction can be modified by the presence of Egr-1 and Pitx1.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cattle
  • Cell Line
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Early Growth Response Protein 1
  • Fushi Tarazu Transcription Factors
  • Gene Expression Regulation / genetics*
  • Genes, Reporter / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Immediate-Early Proteins*
  • Luteinizing Hormone / genetics
  • Luteinizing Hormone / metabolism*
  • Models, Biological
  • Paired Box Transcription Factors
  • Promoter Regions, Genetic / genetics*
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein Subunits
  • Receptors, Androgen / metabolism*
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Estrogen / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Steroidogenic Factor 1
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic / genetics

Substances

  • DNA-Binding Proteins
  • EGR1 protein, human
  • Early Growth Response Protein 1
  • Egr1 protein, mouse
  • Fushi Tarazu Transcription Factors
  • Homeodomain Proteins
  • Immediate-Early Proteins
  • NR5A1 protein, human
  • Paired Box Transcription Factors
  • Protein Subunits
  • Receptors, Androgen
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Estrogen
  • Recombinant Fusion Proteins
  • Steroidogenic Factor 1
  • Transcription Factors
  • homeobox protein PITX1
  • steroidogenic factor 1, mouse
  • Luteinizing Hormone