Among the most mysterious receptors are those nuclear receptors that have no hormone. Resident in liver and in ovaries during pregnancy, the receptor liver related homologue 1 (LRH-1) is active without binding hormone. LRH-1 controls cholesterol and metabolism of steroid hormones. Its closest relative, steroidogenic factor 1 (SF-1), is required for proper male sexual development and affecting endocrine and neuroendocrine tissues. The mechanisms of regulation of these nuclear receptors are not yet known, and their ability to activate transcription of target genes without hormones appears paradoxical. ? ? The goal of this exploratory proposal is to understand the mechanisms of regulation of LRH-1 and SF-1 base line transcriptional activation. In particular, we will analyze, at atomic-resolution, the binding interactions of LRH-1 and SF-1 with their physiological partners that halt activation of these receptors. Critical to biological control of these two nuclear receptors are two mysterious corepressors, small heterodimeric partner SHP and its sibling corepressor Dax-1, themselves nuclear receptors also without hormones. No one has ever before prepared SHP or Dax-1 in a functionally active state for biochemical studies. Abnormalities in functioning and regulation of LRH-1 and SF-1 are associated with numerous human diseases. Recent studies showed a direct linkage between development of a breast tumor and abnormal activity of LRH-1 in breast tissue. ? ? Abnormalities in regulation of SF-1 lead to defects in both male and female sexual differentiation. The studies proposed in this grant application would provide the means for developing selective therapeutics tuning the aberrant transcriptional activity of these nuclear receptors. ? ?
