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Nuclear receptor coactivators modulate hormone-dependent gene expression in brain and female reproductive behavior in rats
Estradiol (E) and progesterone (P) induce the expression of sexual behavior in female rats by binding to their intracellular receptors (ER and PR, respectively) in specific brain regions. Nuclear receptor coactivators, including Steroid Receptor Coactivator-1 (SRC-1) and CREB Binding Protein (CBP), have been shown to enhance ligand-dependent steroid receptor transcriptional activity in vitro. One mechanism by which nuclear receptor coactivators promote gene expression is by bridging the receptor complex with the basal transcription machinery and inducing chromatin remodeling. Although knockout mice have provided some insight into the general function of SRC-1 and CBP in vivo, it is difficult to interpret these data because both SRC-1 and CBP interface with a large family of nuclear receptors. Consequently, the data do not provide information specific to ER and/or PR, or provide information specific to brain region. Therefore, to test the hypothesis that SRC-1 and CBP are important mediators of E and P action on sexual behavior, I decreased coactivator proteins in the ventromedial nucleus of the hypothalamus (VMN) using an antisense technique. I found that reduction of SRC-1 and CBP in the VMN decreased (1) ER-mediated induction of PR expression in the VMN, (2) ER-dependent sexual receptivity as characterized by the lordosis posture, and (3) PR-dependent proceptive behaviors including hopping and darting and ear wiggling. Using pull-down assays to test whether SRC-1 from hypothalamic or hippocampal/cortical extracts interacts with ER and PR, I found that SRC-1 from brain associates with ER and PR when receptors were bound to agonists, but not when bound to antagonists, or in the absence of ligand. Furthermore, the efficiency of the interactions between SRC-1 and ER or PR was dependent upon receptor subtype. Taken together, the present studies suggest that coactivators interact with ER and PR in the brain as they modulate hormone actions in the VMN that regulate sexual behavior.
Molenda-Figueira, Heather A, "Nuclear receptor coactivators modulate hormone-dependent gene expression in brain and female reproductive behavior in rats" (2006). Doctoral Dissertations Available from Proquest. AAI3212742.