Steroidogenesis is acutely regulated in the ovary by gonadotropins. Production of steroid hormones requires synthesis of a cholesterol-shuttling protein to translocate cholesterol from the outer to the inner mitochondrial membrane. The steroidogenic acute regulatory (StAR) protein was demonstrated to be an essential component in the acute regulation of steroid hormone biosynthesis. Compelling evidence for StAR's role in steroidogenesis was established through studies on the disease congenital lipoid adrenal hyperplasia (CAh). CAH patients present with mutations in the StAR gene and lack the ability to synthesize steroids. Targeted disruptions of the StAR gene in mice cause all affected mice (male and female) to present with female external genitalia and exhibit premature death. The long-term objective of this research is to characterize the mechanisms involved in the regulation of StAR to ensure that sufficient amounts of steroid hormones are synthesized for proper ovarian function. The rat StAR promoter gene has been shown to contain regulatory elements through which positive and negative regulatory factors can directly affect StAR transcription. Our laboratory has reported that the transcription factors YY1 and DAX-1 repress StAR gene expression principally through disruption of StAR's interaction with positive regulatory factors. Preliminary data demonstrates that estradiol/estrogen receptors activate StAR transcription and this effect can be enhanced through interactions with SREBP-1a. We hypothesize that StAR gene expression in the ovary is regulated by at least three distinct mechanisms. These include: 1) an alteration in the ratio of YY1 proteins to other positive regulatory factors which leads to the repression of StAR, 2) activation of DAX-1 by PGF2alpha, which can directly or indirectly decrease StAR activation and 3) positive cis- and trans-activating regulation of StAR transcription via estrogen receptors. We propose to examine these mechanisms by the following abbreviated specific aims:
Aim I : To 1) investigate the mechanisms involved in YY1 repression of StAR in the ovary through histone deacetylases/methylases, and through disruption of positive protein-protein interactions, 2) identify regions of YY1 necessary for repression and 3) determine whether methylation of the StAR promoter affects YY1 binding.
Aim II : To determine whether DAX-1 repression of StAR transcription occurs through disruption of positive interactions or recruitment of co-repressors.
Aim III : To define which co-activators or co-repressors are involved in estrogen receptor regulation of StAR. Since studies on patients with CAH and targeted disruption of StAR in mice demonstrate the essential role of StAR in reproductive functions, our studies will provide vital information with respect to the molecular regulation of StAR and identify ovarian factors that are crucial to regulate StAR gene expression in order to maintain adequate amounts of steroidogenesis.
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