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Society for Women's Health Research, Washington, District of Columbia 20036
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ABSTRACT |
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 INTRODUCTION
THE BIRTH OF THE...
THE MOLECULAR BIOLOGY...
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STEROID HORMONE RECEPTOR...
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The field of steroid hormone action is well established, although it is barely more than four decades old. Pivotal experiments in the late 1950s and 1960s showed that hormone-binding components exist within nuclei of target tissues and that steroid hormones act by regulating gene expression, rather than directly influencing enzymatic processes. The understanding that steroid hormone receptors interact with the general transcription machinery and alter chromatin structure came in the 1970s and 1980s, and details of this mechanism continue to be elucidated. In addition, the discovery of rapid cellular responses to steroid hormones has led to the identification of putative membrane-bound steroid receptors that act without affecting gene transcription. As noted in the recent Institute of Medicine report Exploring the Biological Contributions to Human Health: Does Sex Matter?, the effects of steroid hormones and defects in steroid hormone receptor action have a profound impact on human health and disease. Future research directives include the development of potent, selective steroid receptor modulators, the elucidation of nongenomic steroid hormone effects, and further exploration of hormone-genome interactions.
estrogen; progesterone; androgen; coactivators; corepressors
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STEROID HORMONES ARE INVOLVED in various aspects of growth, development, differentiation, reproduction, and homeostasis. They exert their effects by means of steroid hormone receptors, such as estrogen (ER), progesterone (PR), androgen (AR), glucocorticoid (GR), and mineralocorticoid receptors. Steroid hormone receptors belong to the steroid/thyroid hormone receptor superfamily, which includes thyroid hormone (TR), retinoic acid (RAR), and vitamin D3 receptors, as well as "orphan" receptors [e.g., ER-related-1 (ERR-1), ERR-2, and chicken ovalbumin upstream promoter-transcription factor], for which no ligands have yet been found.
All members of the steroid and thyroid hormone receptor superfamily share similar structure consisting of modular domains A through F (from NH2 to COOH terminus; Ref. 38). Each receptor contains a unique A/B region, which is variable in length and sequence between the receptors. The A/B region allows for protein-protein interactions and transcriptional activation of target genes. The cysteine-rich C region contains two zinc fingers important for DNA binding and receptor dimerization. In some receptors, region D contains the nuclear localization signal and/or a transactivation domain. The E region is responsible for several functions, including ligand binding, heat shock protein (HSP) association, receptor dimerization, nuclear localization, hormone-dependent transactivation, and, in some cases, transcriptional repression. The F region is present in few receptors and exhibits minimal regulatory function (38).
This brief historical perspective on steroid hormone action focuses on the discovery and elucidation of the mechanism by which the sex steroid hormones (estrogens, progesterone, and androgens) affect gene expression through direct interaction with nuclear DNA and transcription machinery by means of steroid hormone receptors. We have chosen to limit discussion to the sex steroid hormones because they are the significant players in the development of female- and male-specific traits. Although much research on the sex steroid hormones has focused on their role in reproduction, a recent report issued by the National Academy of Sciences Institute of Medicine (IOM; 40) found that differences between the sexes go well beyond the reproductive system and secondary sex characteristics, to include nearly every tissue and organ in the body. For example, men and women often exhibit different symptoms when having a heart attack, women are more likely than men to recover language abilities after a left-hemisphere stroke, and women are more likely to suffer from autoimmune diseases in general (40). Moreover, the effects of sex steroid hormones begin during embryonic development and continue through the life span, from "womb to tomb," as the IOM report describes it. Thus understanding the roles of the sex steroid hormones during development, in normal physiological processes, and in the etiology and progression of diseases is essential to advancing human (and animal) health. This historical perspective provides a general overview and abridged history of the burgeoning field of steroid receptor action. Because of space limitations, reviews are predominantly cited instead of primary references. The reader is urged to refer to these reviews for more detailed accounts.
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THE BIRTH OF THE FIELD OF STEROID HORMONE ACTION |
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Pivotal experiments performed in the late 1950s and early 1960s, primarily in the laboratories of Gerald Mueller and Elwood Jensen, set the stage for the development of the field of steroid hormone action. Jensen's laboratory showed that tritiated estradiol was specifically taken up and retained in the immature rat uterus, indicating the presence of an "estrogen-binding component" or "estrophilin," later termed "estrogen receptor" by Jensen (14, 25). This was the first time that target tissue specificity was observed for a natural hormone. Also during this period, Mueller's laboratory reported that estrogen treatment induced RNA and protein synthesis. Later, Mueller was able to show that all known uterine responses to estradiol were blocked when either RNA or protein synthesis was inhibited, showing that transcription and translation were required for estradiol's effects (14).
In the mid 1960s, Jack Gorski's laboratory showed that tritiated estradiol bound to the estrogen-binding component and that this complex could be solubilized from rat uterus cell nuclei. Jensen, Gorski, and others then showed that, after estradiol treatment, estradiol traveled from the cytosol to the nucleus (14, 25). For many years, it was thought that ER bound estrogen in the cytoplasm and was then translocated to the nucleus. However, it is now known that ER is a nuclear factor that initiates interaction with estrogen in the nucleus (20). The same holds true for PR, although other members of the steroid/thyroid hormone receptor superfamily appear to have both nuclear and cytoplasmic localization (4).
In the mid to late 1960s, researchers concluded that steroid hormones regulate gene expression (through interaction with cognate receptors), rather than influencing enzymatic metabolism. In 1966, Gorski and Angelo Notides collaborated to show that estradiol treatment resulted in the synthesis of a specific uterine protein (24). Subsequently, Bert O'Malley's laboratory demonstrated steroid-mediated mRNA induction of ovalbumin in response to estrogen and of avidin in response to progesterone (25). The 1960s culminated with the first Gordon Conference on Hormone Action, establishing steroid hormone action as a legitimate and growing field of research (25).
The late 1960s and early 1970s brought an explosion of research on
steroid hormone receptors. In 1972, O'Malley's laboratory was the
first to purify a steroid hormone receptor, PR from chicken, to near
homogeneity. Interestingly, they discovered two isoforms, PR-A and
PR-B. PR-B is >100 amino acids longer (NH2 terminus) than
PR-A, but otherwise the two isoforms are identical. This finding is
consistent between species, with the exception of rabbit, in which PR
exists as a single form (35). Soon after the purification of PR, ER and AR were purified, although it was not until
1996 that a second form of ER, ER-
, was discovered (11,
23).
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THE MOLECULAR BIOLOGY REVOLUTION |
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Molecular elucidation.
With the advent of recombinant DNA and DNA sequencing technologies in
the mid 1970s came the ability to characterize the steroid hormone
receptors and their target genes in more detail. O'Malley's laboratory was the first to clone (1977) and sequence (1978) a target
gene for steroid hormones, ovalbumin from chicken, and soon after came
the discovery by Pierre Chambon's laboratory that the gene contains
exons and introns (25). Cloning of the first steroid
hormone receptor (GR) occurred in 1985 through a collaboration between
Ronald Evans', Michael Rosenfeld's, and Brad Thompson's laboratories. Shortly after this milestone, the receptors for estrogen
(1986; now known to be ER-
), progesterone (1987), and androgen
(1988) were cloned. In humans, the ER- gene resides on chromosome 6, whereas ER- is on chromosome 14 (11). Human PR
localizes to chromosome 11 (18), and the AR gene resides
on the X chromosome, underscoring its necessity for female, as well as
male, development (28).
A model emerges. Through the work of a number of laboratories in the 1980s and early 1990s, a model for steroid receptor action at the level of the gene began to emerge. In 1983, Keith Yamamoto's and Jan-Åke Gustaffson's laboratories demonstrated for the first time that a steroid hormone receptor (GR) binds DNA in a sequence-specific manner. The receptor binding site, now termed the steroid response element (SRE), is located upstream of steroid hormone-regulated promoters. In general, SREs are 15-base pair consensus sequences consisting of two half sites, arranged as 6-base pair inverted repeats separated by a few random base pairs. The SREs for various receptors exhibit significant sequence similarity, with SREs for GR, PR, and AR oftentimes being identical (26). In 1988, O'Malley's laboratory was able to show that receptors bind the SREs cooperatively as dimers, with one receptor molecule at each half site (26). In vitro experiments performed in the mid 1990s demonstrated that receptor binding to DNA is not hormone dependent (22).
In the mid 1980s, Etienne-Emile Baulieu's, David Toft's, and William Pratt's laboratories discovered that inactive steroid hormone receptors interact with a nonhormone protein, later identified as a HSP (HSP90; Refs. 15, 34). HSPs likely stabilize unliganded steroid hormone receptors by preventing folding, aggregation, and DNA binding (13). Steroid hormone receptors are the only members of the steroid/thyroid superfamily known to bind HSPs (1). Experiments performed by the Pratt and Toft laboratories in the late 1980s demonstrated that the dissociation of HSPs from receptors is hormone-dependent (33). In the mid 1980s, steroid hormone receptors were shown to be phosphorylated in a hormone-dependent manner. Edwin Milgrom's laboratory showed that PR is phosphorylated, and with hormone administration, becomes hyperphosphorylated (35). These experiments suggested that steroid hormone receptor action is dependent on phosphorylation status. In the late 1980s and early 1990s, O'Malley's laboratory showed that steroid hormone receptors interact with transcription factor IIB (TFIIB), leading to the hypothesis that steroid hormone receptors facilitate transactivation via protein-protein interactions with general transcription factors. This hypothesis was soon validated when they successfully reconstructed the entire pathway of steroid hormone action in a ligand-dependent, receptor-mediated, cell-free transcription system (25). They showed that ligand-bound receptor (PR) binds the SRE and stabilizes the association of general transcription factors, including TFIIB. This interaction between receptor and general transcription factors allows for the successful recruitment of the polymerase to the promoter and subsequent transcription of the target gene. These discoveries were the culmination of the previous three decades of research and led to a well-supported model for steroid hormone receptor action: ligand binding induces a conformational change in the receptor, releasing HSPs. The receptor undergoes hormone- and DNA-dependent hyperphosphorylation, dimerizes, and binds its target DNA. The binding of the receptor to the SRE allows for the recruitment of general transcription factors and, subsequently, RNA polymerase to begin efficient transcription (13, 35).| |
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Coactivators. In 1989, experiments performed in the laboratories of both O'Malley and Hinrich Gronemeyer showed that overexpression of one steroid hormone receptor results in the inhibition of itself or other steroid hormone receptors. These experiments suggested that other limiting factors, termed "coactivators," might modulate transactivation by steroid hormones. These coactivators are thought to function as bridging factors that, directly or indirectly, facilitate the crucial protein-protein interactions between the steroid hormone receptor and the general transcription machinery to ensure efficient transcription of target genes (38). In addition, several coactivators have been shown to either possess, or interact with proteins that possess, histone acetyltransferase (HAT) activity (31). By facilitating chromatin remodeling, HAT proteins may enhance the formation of stable preinitiation complexes and thus increase transcription of target genes.
Both general coactivators, as well as receptor-specific coactivators exist. Two general coactivators, steroid receptor coactivator-1 (SRC-1) and cAMP response element binding protein-binding protein (CBP), enhance the transcriptional activities of several steroid/thyroid hormone receptors (38). SRC-1 was identified in 1995 by O'Malley's laboratory and was shown to enhance the transcriptional activity of all steroid hormone receptors tested, without altering basal promoter activity. In 1996, William Chin's laboratory showed that SRC-1 interacts with a variety of steroid and thyroid hormone receptors in a ligand-dependent manner, as well as with TATA-binding protein and TFIIB. Subsequently, O'Malley's laboratory discovered that SRC-1 not only has intrinsic HAT activity but also interacts with an additional HAT protein, p300/CBP-associated factor (PCAF), thus giving it a role in chromatin remodeling (31). RU-486, an antagonist of PR, prevents the interaction of SRC-1 with PR, thus discouraging transcription of PR target genes (31). CBP, which was first described by Richard Goodman's laboratory in 1993, interacts with SRC-1 and TFIIB, as well as with PCAF. Receptor-specific coactivators do exist, such as the androgen receptor-associated protein 70, first described by Chawnshang Chang's laboratory in 1996 (38).Corepressors. Not only can the steroid/thyroid hormone receptors activate transcription in the presence of hormone but also they can silence basal promoter activity of target genes in the absence of hormone or in the presence of antagonist. This phenomenon was first observed with TR and RAR, which have been shown to bind cognate DNA response elements in the absence of hormone and repress basal transcription (38). Competition experiments suggested that this silencing activity requires binding of a "corepressor." The corepressors silencing mediator for RAR and TR (SMRT) and nuclear receptor corepressor (N-CoR) were cloned in 1995 (38). These proteins are thought to act by recruiting additional proteins with histone deacetylase activity, thus inhibiting transcription complex formation (8). Agonists, but not antagonists, are able to dislodge corepressors bound to unliganded receptors, thus relieving the silencing function. In the case of a mixed agonist and antagonist, such as tamoxifen (for ER), relief of the silencing functions may depend on the relative ratio of coactivators to corepressors (10, 38).
Evidence for corepressor interaction with the classic steroid hormones is also emerging. Recently, ER has been shown to interact with N-CoR (10). In addition, the surprising observation that human PR-A acts as a transdominant transcriptional inhibitor appears to be due to its interaction with the corepressor SMRT and its inability to interact with coactivators (8). As receptor specific coactivators and corepressors continue to be discovered, researchers can better understand how steroid hormone receptors alternate between gene silencing and transactivation functions. The interesting biology of steroid hormone receptor action on gene expression is dependent on several factors, including the nature of the ligand (agonist or antagonist), the isoform or subtype of receptor, the nature of the steroid response element, and the character and balance of coactivators and corepressors. These factors confer tissue and gene specificity and begin to explain the complexity and diverse cellular roles of steroid hormone receptors.| |
STEROID HORMONE RECEPTOR DEFECTS |
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Much has been learned about the functions of steroid hormone receptors by studying gene knockouts and naturally occurring mutations. These studies allow researchers to gain insight into the causes of many diseases, such as cancer (breast, endometrial, prostate), osteoporosis, and androgen insensitivity, to name a few. By understanding the mechanism of action of steroid hormone receptors and their structure-function relationships, researchers can better design drugs (e.g., tamoxifen, raloxifene, RU-486) to treat debilitating diseases caused by defects in steroid hormone receptor action.
ER defects.
In 1993, Oliver Smithies' and Kenneth Korach's laboratories
collaborated to create ER- knockout mice. Female ER- knockout mice exhibit severe reproductive and behavioral phenotypes, including complete infertility, absence of breast tissue development, and absence
of sexual response. Male mice exhibit a significant reduction in
fertility, and both female and male mice have altered bone densities
(39).
mutation was described as exhibiting estrogen
resistance, tall stature, low bone mineral density, unfused epiphyses,
insulin resistance, and abnormal gonadotropin secretion. Taken
together, these phenotypes suggest ER- is important for bone
maturation and mineralization, normal reproduction, and sexual behavior
(39).
In 1998, the Smithies, Gustafsson, and Korach laboratories collaborated
to create ER- knockout (BERKO) mice. Female BERKO mice are fertile
and exhibit normal sexual behavior but have fewer and smaller litters
than wild-type mice due to reduced ovarian efficiency. Older male BERKO
mice display signs of prostate and bladder hyperplasia. Both male and
female BERKO mice display abnormal breast epithelial growth and develop
severe cystic breast disease as they age. Also, mice lacking both
ER- and ER- have been generated and survive, although both sexes
are infertile. On the basis of these results, it can be concluded that
ER- is of importance for normal reproduction and ovarian function,
prostate growth control, and may have a protective role in the breast
(11).
Mutations in genes regulated by and whose products regulate ER- and
ER- are associated with breast and ovarian cancer (6, 7), and estrogen deficiencies contribute to osteoporosis and cardiovascular disease (16, 40). Selective estrogen
receptor modulators (SERMs), such as tamoxifen and raloxifene, which
have mixed estrogenic and antiestrogenic properties, have been
developed to treat and prevent these diseases, and more are in
development. Tamoxifen was developed in the late 1970s to treat breast
cancer via its antiestrogenic properties. In addition, tamoxifen has been shown to be chemoprotective, reducing the risk of breast cancer by
almost 50% in women at high risk of getting the disease (30). Tamoxifen also produces beneficial estrogenic
effects in other target tissues, such as bone, thus preventing
postmenopausal osteoporosis. However, the estrogenic properties of
tamoxifen are not limited to the bone and thus cause unwanted side
effects such as increased risk of endometrial cancer. Raloxifene, a
second-generation SERM developed in the 1980s, exhibits bone-beneficial
actions without the toxic side effects caused by tamoxifen (5,
20, 27). Clinical trials have also demonstrated that raloxifene has beneficial estrogenic effects on the cardiovascular system, including reducing low-density-lipoprotein and total cholesterol levels
(32). In addition, the ongoing Study of Tamoxifen and Raloxifene trial is attempting to determine whether raloxifene will
also be useful as a breast cancer chemoprotective agent
(30). The future of SERM development relies
on the further elucidation of ER action, and the understanding of how
drugs work in each target tissue.
PR defects. The mid to late 1970s and early 1980s brought the discoveries that abnormal action of PR played a role in disease, specifically breast cancer, uterine fibroids, and endometriosis (3). Subsequently, antiprogestins, notably RU-486, began being synthesized to treat PR-related diseases. During the early 1980s, it was discovered that RU-468 binds to the rat ovary PR, and its direct antiprogesterone action on the uterus was thought to induce menstruation and early abortion (37). The antiprogestin activity of RU-486 has been used for the treatment for meningiomas and endometriosis and as a postcoital contraceptive (3).
The mid 1990s brought the development of PR knockout mice. Because PR is induced by estrogen via ER, it was unclear which reproductive effects are due to PR or ER. By knocking out PR, it became clear that this molecule is necessary for proper development of the reproductive organs and mammary glands, as well as induction of the sexual response in females. Males show no observable effects (19). The development of the SRC-1 knockout mouse later in the decade showed the importance of this molecule in progesterone action, because the animals exhibit partial hormone resistance in the uterus, mammary gland, prostate, and testis (31).AR defects.
Androgens, primarily testosterone and its active metabolite
dihydrotestosterone (DHT), play crucial roles in development and maintenance of male phenotype (2), and evidence is
accumulating for a crucial role for testosterone in female biology. A
single AR appears to bind both testosterone and DHT (2).
Testosterone is rapidly converted to DHT by 5-reductase in
androgen-sensitive tissues such as the prostate (28), and
the AR binds DHT with higher affinity than testosterone.
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FUTURE DIRECTIONS |
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Despite the great deal of information about steroid hormone action now known, many questions remain unanswered relating to receptor activation, regulation, and protein interactions. Since the early 1990s, it has been known that ligand-independent activation of PR and ER can occur (25). However, the full implications of these observations are not yet understood, although researchers have suggested that this type of activation may be associated with breast and uterine cancers and may have ramifications for learning, memory, and behavior. In addition, multiple interactions have been observed between steroid hormone receptors and other superfamily members, growth factors, and protein kinases (17). Further elucidating how these diverse interactions are involved in the regulation of gene expression and cell proliferation will aid in the detection and treatment of various diseases and conditions.
Yet another question deserving of further attention is how rapid
cellular responses to steroid hormones, which cannot be explained by
classic hormone transactivation, occur. This "nongenomic" mechanism was proposed as early as 1975 by Richard Pietras and Clara Szego to
involve membrane-bound steroid receptor-induced increases in intracellular second messengers (36). In recent years,
evidence has accumulated for the presence of classic ERs (both ER-
and ER-) at the membrane of specific types of cells (29,
36). In addition, a putative nonnuclear, membrane form of PR has
been cloned (36). Understanding how membrane-bound and
classic steroid hormone receptors interact to govern complex
hormone-mediated cellular responses promises to yield therapeutic
options for diverse conditions such as cancer and neurodegenerative and
cardiovascular diseases.
The understanding that sex steroid hormones exhibit effects on tissues outside the reproductive tract, such as bone, heart, and brain, underscores the necessity of including both male and female animals and humans in research studies and of analyzing resulting data by sex. Such analyses are imperative to elucidating important physiological differences and similarities between the sexes. Forums such as the Journal of Applied Physiology's miniseries on Genome and Hormones: Gender Differences in Physiology will surely advance the understanding of the relationships between the molecules that affect and are affected by steroid hormones and animal and human health.
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ACKNOWLEDGEMENTS |
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We thank Carol Sartorius, Ulla Hansen, and Paul Bertics for critical comments on the manuscript.
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FOOTNOTES |
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Address for reprint requests and other correspondence: R. M. Videaver, Society for Women's Health Research, 1828 L St. NW, Suite 625 Washington, DC 20036 (E-mail: Regina{at}womens-health.org).
Received 1 June 2001; accepted in final form 25 July 2001.
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