Nuclear receptors are a family of ligand-regulated transcription factors that are activated by steroid hormones, such as estrogen and progesterone, and various other lipid-soluble signals, including retinoic acid, oxysterols, and thyroid hormone. Unlike most intercellular messengers, the ligands can cross the plasma membrane and directly interact with nuclear receptors inside the cell, rather than having to act via cell surface receptors. Once activated, nuclear receptors directly regulate transcription of genes that control a wide variety of biological processes, including cell proliferation, development, metabolism, and reproduction.
Although nuclear receptors primarily function as transcription factors, some have also been found to regulate cellular functions within the cytoplasm. For example, estrogens act through the estrogen receptor in the cytoplasm of endothelial cells to rapidly activate signaling pathways that control vascular tone and endothelial cell migration.
Nuclear receptors share a common structure, comprising a highly variable amino-terminal domain that includes several distinct transactivation regions (the A/B domain; also referred to as AF1 for activation function 1), a central conserved DNA-binding domain that includes two Zn fingers (the C domain), a short region responsible for nuclear localization (the D domain), and a large fairly well-conserved carboxy-terminal ligand-binding domain (the E domain, or LBD) that also contributes to interactions of the subset of nuclear receptors that form heterodimers. Some also possess a highly variable carboxy-terminal tail (the F domain) that in most cases has unknown functions.
A characteristic feature of nuclear receptors with respect to their integrative roles in development and homeostasis is their ability to regulate different genes in different cell types. For example, estrogen receptors regulate different sets of genes in the brain, breast, and uterus that contribute to the distinct functions of those organs. Recent studies indicate that tissue-specific responses are a consequence of binding of nuclear receptors to enhancer elements that are selected in a cell-specific manner. Cell-specific enhancer selection is conferred by the key lineage-determining factors for each cell type, which interact in a collaborative manner to generate open regions of chromatin that provide access points for signal-dependent transcription factors.
Given the wide variety of processes controlled by nuclear receptors, their dysregulation can contribute to numerous diseases, including cancer, diabetes, and infertility. However, because they bind to small molecules, they represent promising therapeutic targets for which selective agonists and antagonists can be engineered. Because nuclear receptors regulate many genes in many tissues, synthetic ligands usually show beneficial therapeutic effects and unwanted side effects that limit clinical use. Major goals in the nuclear receptor field therefore include attaining a better understanding of the mechanisms underlying their actions in specific cell types and ways in which to selectively modulate their activities.