Hormonal Regulation

The nuclear receptors are a large group of related proteins that mediate many of the effects of steroid hormones, thyroid hormone, vitamin D3, the vitamin A derivative retinoic acid, and modified forms of cholesterol, such as hydroxycholesterol and bile acids. The number of nuclear hormone receptor genes varies widely among animals. Humans and other vertebrates have about forty-nine receptor genes, whereas the nematode Caenorhabditis elegans, with only 959 cells in the adult worm, has more than 250 receptor genes. This was a somewhat unexpected finding, and it led to the speculation that Schematic depiction of how the retinoic acid receptor activates transcription of target genes. In the absence of retinoic acid, the receptor interacts with the corepressor complex to condense chromatin and silence transcription from target genes. In the presence of retinoic acid, the corepressor complex dissociates and the receptor can then interact with a coactivator complex that leads to chromatic decondensation and subsequent activation of target genes. The active and repressed states exist in a dynamic equilibrium that is regulated by the presence of retinoic acid. C. elegans may use nuclear hormone receptors to regulate processes that are controlled by different transcription factors in vertebrates.

The classical steroid receptors are all quite similar to each other, and they all function as homodimers—a complex of two identical proteins. With the exception of the estrogen receptor, all of these receptor homodimers bind to exactly the same target DNA sequences. For this reason, high levels of one hormone may cause inappropriate activation of another pathway and multiple consequences.

It is currently unclear how one receptor (e.g., the glucocorticoid receptor) distinguishes its correct target genes from those of other receptors (e.g., the progesterone receptor), when multiple receptors are present in the same cell. Estrogens, progesterone, and androgens are important steroid hormones that influence many aspects of later development.

The estrogen receptor is expressed in the brain, kidney, liver, and lungs, and throughout the female reproductive tract. Interestingly, the estrogen receptor is also present and required in male reproductive tissues. The major human estrogen, 17-βestradiol, activates the receptor to regulate cell proliferation in, for example, the uterus. The progesterone receptor is also important for female development, with its effects restricted to the female reproductive tract and mammary tissue.

The androgen receptor is primarily responsible for male development and secondary sexual characteristics, such as muscle mass. The major hormone acting through this receptor is dihydrotestosterone (DHT). The androgen receptor is also the major receptor targeted by so-called anabolic steroids, which function by mimicking the activities of DHT on muscle growth. Some predictable and unfortunate consequences of increasing the circulating levels of testosterone-like molecules include atrophy of the testes (since they sense high levels of testosterone and react by shutting down their own production) and the development of female secondary sexual characteristics, such as breasts, in men (because excess DHT is converted to estradiol).

The largest and most diverse group of nuclear receptors contains those that function as heterodimers, meaning they are composed of two different parts. Each heterodimer is composed of one unique receptor protein and one protein common to the whole group, called the 9-cis-retinoic acid receptor (RXR). There are nine distinct hormone-regulated receptor-signaling pathways wherein RXR is used as a common heterodimeric partner.

One of these is the retinoic acid receptor (RAR), which binds with alltrans retinoic acid, a vitamin A derivative, to regulate many important aspects of early embryonic development, including limb formation, central nervous system patterning, growth and differentiation of many tissues, hematopoiesis, and eye, brain, and craniofacial development. Since retinoic acid affects so many important developmental processes, too much or too little retinoic acid has profound effects on early development.

Another RXR partner is the steroid and xenobiotic receptor (SXR). Steroid and xenobiotic ligands for SXR regulate the breakdown of foreign chemicals by degradative enzymes in the liver and intestines, protecting the body from toxic chemicals and bioactive dietary compounds. SXR is known to directly regulate the transcription of genes such as CYP3A4, which mediates the breakdown of 60 percent of clinically useful drugs, as well as the transcription of the multidrug resistance protein MDR1, which transports drugs out of the cell. Thus, SXR is a key mediator of the body's defense system against foreign chemicals, controlling both their metabolism and clearance from the cell.