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Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106-4965
Synthesis of LH is suppressed by feedback from gonadal steroids.
Previously, we demonstrated that 779 bp of the bovine LHß 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 LHß promoter when examined in a gonadotrope-derived
cell line. Additional studies with mutated bovine LHß 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-1
LBD) each
individually rescued androgen-mediated suppression of the bovine LHß
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 LHß 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 LHß
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.
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