Molecular genomics of progestin actions

Progesterone is a member of a family of steroid hormones that act throughout the body to regulate homeostasis, development, reproduction, and behavior. Many of these biological effects of progesterone are mediated through the progestin receptor (PR), which is a member of the steroid/nuclear receptor superfamily of transcriptional activators. PR can act by a classic genomic mechanism that involves binding to DNA and transcription of target genes. Nuclear receptor coregulators are critical in modulating transcriptional activity of steroid receptors, including PR. Herein, we review recent findings from studies in cell lines and in brain on classic genomic mechanisms of PR action, including the function of nuclear receptor coregulators and chromatin remodeling. Recent studies indicate that PR can function at the membrane and can have rapid effects in the cytosol as mediators of growth factor-initiated signaling pathways. We have thus highlighted the importance of phosphorylation of PR by rapidly activated cytoplasmic protein kinases in breast cancer models and in brain and behavior. Integration of cytoplasmic signaling events with PR nuclear actions is predicted to have profound effects on PR action. The implications for these classic genomic and nongenomic signaling pathways on the biological functions of PR are discussed.