Hormonal Regulation

All types of cells are capable of receiving signals from their environment and mounting an appropriate response to the signal, such as chemotaxis toward a nutrient source or toward other cells emitting a pheromone . The key difference between microorganisms and more-complex plants and animals is that the former are largely independent, with each cell in contact with the environment. In contrast, more complex plants and animals are self-contained entities whose interior is mostly insulated from the environment. Animals have complex organ systems, with each organ specialized for a particular function. Therefore, the survival of the organism depends on the precise regulation of growth, differentiation, and metabolism in different groups of cells throughout the animal.

The endocrine system is the set of glands and other tissues responsible for coordinating cellular growth and differentiation, many aspects of

reproduction and embryological development, the maintenance of homeostasis , and a variety of cyclical phenomena (e.g., reproductive cycles). Because these varied processes require coordinated gene expression, they are regulated by a large and diverse group of inter-and intracellular signaling pathways.

The primary mediators of these pathways are a large group of chemical messengers, called hormones, produced by specialized cells in response to physiological requirements. Many of these specialized cells are located in endocrine glands. Some of the most well-known endocrine glands are the pituitary (which produces many important hormones, such as ACTH), the thyroid (which produces thyroid hormone to regulate metabolic rate), the adrenals (which produce glucocorticoids to regulate blood sugar and stress, and which also produce epinephrine, or adrenaline), the testes (which produce testosterone), and the ovaries (which produce estrogens and progesterone).

Hormones may need to act at different distances from their source, depending on the requirements of the organism, and they can be broadly classified according to the distance across which they signal. Endocrine hormones (e.g., adrenocorticotropic hormone) are produced by endocrine glands (in this case the pituitary gland, located at the base of the brain) at a distance from their site of action (in this case adrenal glands, sitting atop the kidneys) and must be transported throughout the body via the circulatory system. Paracrine hormones, such as the prostaglandins that mediate local inflammatory processes, are produced near their site of action. Autocrine hormones, such as interleukins, act on the cells that produce them, in this case the white blood cells of the immune system.

Hormone Receptors

Regardless of the distance across which a hormone acts, only those cells that contain a specific receptor can respond to the corresponding hormonal signal. The expression of receptors only in the target cells ensures that these (and only these) cells respond in the appropriate way to the hormone, despite the possible presence of a large number of other hormones in the immediate surroundings.

In addition to the distance across which they act, hormones may be further divided into two large groups based on where in the target cell the hormone receptors are located. The first class consists of extracellular hormones that act via specific cell-surface receptors. Most hormones of this family are proteins (such as insulin, interferons, interleukins, and growth factors), fatty acid derivatives (such as prostaglandins and leukotrienes), or amino acid derivatives (such as serotonin and melatonin).

Extracellular hormones bind to specific receptors on the cell surface, triggering a chain of events inside the cell. These events may include the modification (e.g., phosphorylation or dephosphorylation) of one or more "second messengers"—small molecules that act inside the cell to continue the signaling cascade. In addition to any other short-term effects they may have, virtually all hormonal signaling processes culminate in a change in the expression of a set of target genes. Depending on the cell, the transcription of these genes may be increased or decreased, or be turned completely on or turned off, in response to the presence of the hormone.

The other major class of hormonal signals consists of small, typically fat-soluble molecules that are able to diffuse freely into cells. Once inside the cell, the hormone binds to its receptor to directly regulate the expression of target genes. The hormone-receptor complex is a functional transcription factor that in most cases leads to the expression of its target genes. This modulation primarily occurs directly, via binding of the hormone-receptor complex to target DNA sequences, although additional regulation can occur indirectly, via interaction with other transcription factors.

Since the vast majority of these receptors are always in the nucleus, the family is referred to as the "nuclear hormone receptor superfamily." It is also often also called the "steroid receptor superfamily," because steroid receptors were the first of this family to be identified. Steroid hormones include testosterone, progesterone, and the estrogens. The discussion that follows will focus on hormones that interact with nuclear receptors to directly influence gene expression.

Nuclear Receptors and Their Hormones

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 thatC. 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.

Nuclear Hormone Receptors and Transcriptional Regulation

As noted above, nuclear receptor hormones generally act as transcription factors to increase transcription of their target genes. They do this by increasing the rate at which RNA polymerase binds to the target gene's promoter . This occurs in several steps.

The binding of a hormone to the receptor triggers the assembly of other proteins to form a "coactivator complex." The hormone-receptorcoactivator complex binds to a specific DNA sequence (called the hormone response element, a type of transcriptional enhancer). This complex then alters the local DNA structure by directly or indirectly chemically modifying the histones . These modifications open up the DNA, increasing access to the target genes and thereby allowing RNA polymerase and other (general) transcription factors to reach the gene promoter region. Additionally, the hormone-receptor-coactivator complex can directly interact with general transcription factors to help form a "preinitiation complex" of proteins on the target gene promoter. RNA polymerase then interacts with this complex, and the transcription of the gene into mRNA begins.

All hormone-regulated nuclear receptors activate transcription in this manner. Some, such as the steroid receptors, exist in cells as cytoplasmic complexes with "chaperone proteins," such as HSP90, and are excluded from the nucleus in the absence of the hormone. In the presence of hormone, the complexes dissociate, and the receptors dimerize and are transported to the nucleus, where they activate transcription.

Other receptors, such as the retinoic acid, thyroid hormone, or vitamin D receptors, are always found in the nucleus and interact with their specific target genes in the presence or absence of the hormone. When the hormone is absent, the receptor interacts with "corepressor" proteins. The complex of receptor and corepressor interacts with histone deacetylases, leading to local chromatin condensation and silencing of the target gene. Hormone binding leads to a change in the three-dimensional structure of the receptor, causing dissociation of the corepressor complex and leading to the recruitment of the coactivator complex, which enables the target gene to be transcribed.

The Importance of Hormone Concentration

Because the hormones that act through nuclear hormone receptors are nearly all fat-soluble, they are readily absorbed into the body, freely transported, and stored and accumulated in fatty tissues. Steroids, retinoic acid, thyroid hormone, and vitamin D3 are active at extremely low concentrations, ranging from about 0.3 to 30 parts per billion, with 3 parts per billion considered a physiological concentration for retinoic acid and many steroids. Since the hormones are present and act at such low concentrations, it is critical that their levels be precisely regulated. Consequently, hormone synthesis and degradation is regulated by the activity of specific biosynthetic and catabolic enzymes .

It should also be noted that some chemicals in the environment and natural compounds found in the diet can affect the activity of hormone receptors, particularly the estrogen receptor. Such interaction can potentially lead to disturbances in hormone homeostasis and inappropriate regulation of target genes. These xenobiotic "endocrine disrupting chemicals" have the potential to impact many body systems by inappropriately activating or interfering with the activity of hormone receptors. As a result, endocrine disruption is a growing concern that is being studied intensively in many laboratories around the world.

see also Chaperones; Roundworm: Caenorhabditis Elegans ; Signal Transduction; Transcription Factors.

Bruce Blumberg

Bibliography

Chawla, A., et al. "Nuclear Receptors and Lipid Physiology: Opening the X Files." Science 294 (2001): 1866-1870.

Evans, R. M. "The Steroid and Thyroid Hormone Receptor Superfamily." Science 240 (1988): 889-895.

Kliewer, S. A., J. M. Lehmann, and T. M. Willson. "Orphan Nuclear Receptors: Shifting Endocrinology into Reverse." Science 284 (1999): 757-760.