Nuclear receptor Background
Nuclear receptors are transcription factors that regulate gene expression upon binding to their cognate ligands. The ligands are typically small lipophilic chemicals than can penetrate cell and nuclear membranes, thus the signaling relays from ligands to nuclear receptors play important roles in coordinating intracellular transcriptional responses to extracellular and environmental stimuli. As such, nuclear receptors are essential for maintaining the homeostasis of various biological systems and their dysregulation often leads to diseases, such as metabolic disorders and cancers. As a major class of transcriptional regulators in metazoans, there are 48 nuclear receptors identified in humans. The identification of nuclear receptors stands as a great example of how we have been rewarded with groundbreaking therapies from making novel biological discoveries driven by our curiosity to explore the mystery of ourselves.
History and Discovery
The term “hormone” originated in 1905 by EH Starling, thus giving a name to and fostering further work on the concept of chemical messengers that travel and communicate between different organs in the body. Steroid hormones, all derivatives of cholesterol, were isolated and studied shortly thereafter in the early twentieth century and were known to regulate many physiological processes. For example, the purification of cortisone and its observed anti-inflammatory effects, the isolation of thyroxine and its upregulation of pulse and metabolism, as well as the extraction of pancreatic insulin and its initiation of anti-diabetic activity. These hormones were known to be associated with a variety of diseases, and by the 1950s glucocorticoids were commonly used therapeutically. However, the targets of these hormones remained intangible, and it was not until a few key experiments that hormones could be linked to transcriptional control. Radiolabeled-hormones enabled the discovery of cytoplasmic proteins that would translocate to the nucleus upon binding estradiol in uterine tissue. Similar work in Drosophila showed that pulses of ecdysone, the insect molting hormone, trigger subsequent chromosomal puffing activity. A host of studies in the 1970s and early 1980s identified high affinity receptors for the steroid hormones as well as their ability to associate with and manipulate the genome. However, the field’s most critical advance came with the cloning of the glucocorticoid and estrogen receptors. Soon after, the discoveries of the retinoic acid receptor and the insect ecdysone receptor made the concept of an evolutionarily conserved nuclear receptor superfamily concrete.
With almost 50 nuclear receptor genes in the human genome, this superfamily displays a vast diversity in ligand, function and transcriptional mechanism. Due to this wide assortment of members, several classification systems exist for their characterization. One noteworthy division separates the nuclear receptors into two classes: the classic receptors and the orphan receptors. As may be deciphered from the name, the classic nuclear hormone receptors bind ligand at high affinity, while the orphan nuclear receptors initially lacked a known endogenous ligand. Interestingly, this distinction between classic and orphan nuclear receptors represents a shift from the historic approach of endocrinology to a concept termed “reverse endocrinology”. In more traditional methods, hormones were identified based on their physiological effects, and then subsequently their target (or classic) receptors were discovered. However, since the ability to clone nuclear receptors, many were found without a known ligand, thus triggering the search in reverse. The first example of such a success was retinoid X receptor (RXR) and its high affinity ligand 9-cis retinoic acid. Several other orphan nuclear receptors were “adopted” in this way; however their associated endogenous ligands did not always bind at high affinity. For example, the peroxisome proliferator-activated receptors (PPARs), also initially described as orphan receptors, actually recognize several fatty acids and their metabolites at physiological concentrations, and are thought to act as promiscuous lipid sensors rather than being married to one high-affinity steroid hormone. Most orphan nuclear receptors are in fact now adopted, however a few are still considered “true orphans”, and the search continues.
Another means of classifying nuclear receptors is by their sequence and sequence-derived assumed phylogeny, and is perhaps the most standardized and official of the classification systems. This divides the human nuclear receptors into six evolutionary subfamilies: 1) thyroid hormone receptors (TRs), retinoic acid receptors (RARs), RAR-related orphan receptors (RORs), vitamin D receptor (VDR), peroxisome proliferator-activated receptors (PPARs), revErb receptors, liver X receptors (LXRs), farsenoid X receptors (FXRs), pregnane X receptor (PXR), and constitutive androstane receptor (CAR); 2) retinoid X receptors (RXRs), hepatocyte nuclear factor 4 receptors (HNF4s), testicular receptors (TR2, TR4), tailless-like receptor (TLL), photoreceptor cell-specific nuclear receptor (PNR), chicken ovalbumin upstream promoter transcription factors (COUP-TFs), and V-erbA-related protein (EAR2); 3) estrogen receptors (ERs), estrogen-related receptors (ERRs), glucocorticoid receptor (GR), mineralocorticoid receptor (MR), progesterone receptor (PR), androgen receptor (AR); 4) nerve growth factor 1B (NFG1B), nuclear receptor-related 1 protein (NURR1), neuron-derived orphan receptor (NOR1); 5) steroidogenic factor (SF1) and liver receptor homolog (LRH-1); 6) germ cell nuclear factor (GCNF). There are two members of the nuclear receptor superfamily that do not fit into any of these six groups, DAX-1 and SHP, as they differ significantly from the rest in both structure and function. Thus, they have been categorized into a “0” subfamily by this system. The nomenclature code accompanying this classification consists of NR, followed by the subfamily number (0-6), followed by the group and gene numbers.