Nuclear receptor function

Nuclear receptors coordinate the transcription of gene networks in response to binding of ligands and play critical roles in nearly every aspect of vertebrate development and adult physiology. In addition to being regulated by ligands, multiple studies have demonstrated that cellular signaling in response to hormones and metabolic and nutritional status, causes posttranslational modifications in nuclear receptors and that such alterations affects protein interactions, DNA binding and transcriptional activity. However, it is currently largely unclear how ligand binding affects posttranslational modifications and vice versa, and also unknown how these regulatory events cooperate to induce conformational changes and overall transcriptional activity. Dysregulation of nuclear receptors is the underlying mechanism in the development of a number of pathological conditions, and the wealth of data on the biochemical properties of nuclear receptors that has accumulated, and will continue to accumulate, through basic science is fundamental for developing novel pharmaceutical therapies.

We have focused our research to understand the biology of the nuclear receptor steroidogenic factor 1 (SF-1). SF-1 expression is primarily restricted to major steroidogenic organs, i.e. adrenal cortex and gonads, but also seen in the pituitary and in the ventromedial hypothalamus (VMH). Targeted deletion of the Sf1 gene cause adrenal and gonadal agenesis and nearly immediate postnatal death due to respiratory distress caused by glucocorticoid deficiency. Amplification and overexpression in childhood adrenocortical tumors, supports the central role of SF-1 pathways in human endocrine development and disease. SF-1 binds phospholipids in its ligand-binding pocket and exists as a phosphoprotein in sterodiogenic cells.   
          
Thus, SF-1 is an excellent model molecule for studies that aim to reveal novel aspects as to how nuclear receptors integrate ligand binding, signal transduction and activation of cell-specific genes.