A New "New" Syndrome in the New World: Is Multiple Postreceptor Steroid Hormone Resistance Due to a Coregulator Defect?

George P. Chrousos

Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1862

Address correspondence and requests for reprints to: George P. Chrousos, M.D., Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1862. E-mail: chrousog{at}mail.nih.gov


    Introduction
 Top
 Introduction
 References
 
IN THE LAST third of this century, the basic principles of the mechanism of action of steroid hormones, including glucocorticoids, mineralocorticoids, androgens, estrogens, and progesterone, were defined and clinical and/or experimental models of steroid hormone resistance syndromes were described (1, 2) (Table 1Go). In the late 1970s and early 1980s, we realized that the squirrel monkey, a small New World primate species that we initially thought of as a model of glucocorticoid "resistance" (3), was, in fact, characterized by resistance to each and every steroid hormone plus to the sterol hormone Vitamin D (2, 3) (Table 1Go). We also found that this "pansteroid/sterol resistance" was not limited to the squirrel monkey but was a general feature of as many New World primates as we could study at the time. In the 1984 Lawrentian Hormone Conference, the late Mortimer Lipsett and myself suggested that "it is possible that the concurrent alterations of the steroid receptor systems in New World primates reflect some fundamental change in the chromatin proteins or DNA sequences involved in steroidal regulation of gene transcription, putatively common (nonclass-specific) to the different steroid hormones" (4).


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Table 1. Steroid hormone-resistance syndromes

 
In this issue of The Journal of Clinical Endocrinology & Metabolism, New et al. (5) describe two sisters with multiple, partial steroid resistance, whose pathological manifestations were those originally associated with isolated generalized partial glucocorticoid resistance (2) (Table 1Go). This study is the first of a human multiple steroid resistance syndrome and is an excellent example of astute clinical observation and intimate knowledge of the physiology and molecular biology of steroid hormones.

Starting in 1985, the receptors for each of the steroid hormones were cloned and sequenced and found to belong to the Type 1 subclass of classic nuclear receptors, which together with receptors of the Type 2 subclass (including the receptors for Vitamin D, thyroid hormone, retinoids, rexinoids, and farsanoids) and an ever expanding list of orphan receptors, constitute the superfamily of nuclear hormone receptors (6, 7). Generally, nuclear receptors are homologous modular proteins with a carboxyterminal ligand-binding domain (LBD), a middle DNA-binding domain (DBD), and a variable amino-terminal domain (NTD) (6, 7, 8) (Fig. 1Go). The latter is quite long and nonhomologous in steroid hormone receptors. It contains a strong independent transactivation domain (AF1 or {tau}1) and is important for adding specificity to receptor action. The DBD has two DNA-binding "zinc-fingers" and contains also a dimerization and a nuclear localization domain (NLS1). The LBD, in addition to binding the hormone, has a second transactivation domain (AF2 or {tau}2), a second nuclear localization sequence (NLS2), a heat shock protein 90-binding domain, a corepressor domain important for silencing of the receptor, and domains that interact with other nuclear transcription factors, such as the cjun-cfos and nuclear factor (NF)-{kappa}B heterodimers.



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Figure 1. Linearized and simplified structure of a nuclear hormone receptor on which the N-terminal (immunogenic) (NTD), DBD, and LBD are shown, along with the transactivation function AF1 ({tau}1) and AF2 ({tau}2) domains, the corepressor-binding domain, and the various interacting coactivators and corepressors, respectively. The autonomous strong AF1 pertains to the type 1 or classical receptor subclass comprised by the receptors for glucocorticoids, mineralocorticoids, androgens, estrogens, and progesterone.

 
It seems that the nonligand-bound glucocorticoid and mineralocorticoid receptors normally reside in the cytoplasm, in association with heat shock proteins; they translocate into the nucleus on ligand binding. In contrast, the unbound androgen, estrogen, and progesterone receptors are mostly localized in the nucleus. Ligand binding or other posttranslational modifications, such as serine phosphorylation, are necessary to make steroid receptors transcriptionally active in either case (7, 9, 10).

The ability of the ligand-bound steroid receptors to transactivate a steroid-responsive gene depends on the presence of AF1- and AF2-interacting, "bridging" nucleoproteins, the coactivators that have chromatin-remodeling and other enzymatic activities (11, 12) (Figs. 1Go and 2Go). The known coactivators of steroid receptors belong to several families (Table 2Go). The p160 family and the recently described riboprotein coactivator steroid receptor activator (SRA) include members whose activities are limited to nuclear receptors (11, 12, 13). The CREB-binding protein (CBP)/p300 family of coactivators and the CBP/p300-associated PCAF are important for other signal transduction systems as well, including the protein kinase A-cAMP-CREB, the growth factor-cfos/cjun, the growth factor/cytokine Jak-STAT, and the cytokine-NF{kappa}B pathways. Because of their wider functions, CBP and p300 have been also called cointegrators.



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Figure 2. Putative corepressor (left) and coactivator (right) transcription initiation complexes for nuclear receptors. The former are associated with transcriptionally inaccessible chromatin via deacetylation of histone tails and condensation of the DNA strands around the nucleosomes; the latter are associated with transcriptionally accessible chromatin via acetylation of histone tails and decondensation of DNA. The latter complex is succeeded by further accumulation of protein complexes essential for further interaction with and activation of the polymerase II machinery. Defective coactivator or excessive corepressor activity could lead to nuclear hormone resistance affecting multiple nuclear hormonal receptor systems. Protein X, unknown corepressor complex cofactors; protein Y, unknown coactivator complex cofactor(s).

 

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Table 2. Recently described coregulators of nuclear receptors

 
Both the p160 and CBP/p300 coactivators have multiple amphipathic LXXLL signal sequences (the coactivator motifs), which, on binding the ligand, serve as interfaces between these coactivators and a hydrophobic cleft formed by {alpha}-helix 12 of the nuclear receptors (12, 14). p160 proteins may also interact directly and/or via the riboprotein SRA with the AF1 domain (10, 13, 15). The p160, CBP/p300, and PCAF proteins all have histone acetylase (HAT) activity, which loosens the DNA strands from the nucleosomes and allows the transcription initiation complex of RNA-polymerase II and its ancillary components, the transcription activation factors (TAF), to initiate and promote transcription (11, 15).

Nuclear nonligand-bound steroid receptors are kept inactive by association to another group of nuclear proteins, the corepressors (11, 16) (Fig. 1Go and Table 2Go). The corepressor complex contains one or more of several histone deacetylases (HDAC) that function as condensers of the nucleosomes and, hence, as silencers of the transcriptional activity of the steroid receptors (Fig. 2Go). Collectively, coactivators/cointegrators and corepressors have been called coregulators of steroid receptors. Their use by steroid and other nuclear receptors is characterized by varying degrees of relative specificity and combinatorial flexibility. Also, their relative abundance may vary from tissue to tissue and can be stoichiometrically limiting for some but not other nuclear receptors and other factors in a particular tissue. For example, the mutual inhibition of glucocorticoid receptor and NF-{kappa}B seems to be due to competition for common coactivators (17). On the other hand, the SRC-1 knockout mouse suffers from a mild, subclinical form of multiple steroid hormone resistance syndrome, apparently as a result of compensatory elevations of SRC-2 replacing some of the missing SRC-1 activity (18). In contrast, the CBP and p300 knockout mice seem to have major distinct pathologies, CBP cannot fully compensate for the absence of p300, and compound heterozygous mutants for CBP and p300 invariably die in utero (19). These findings suggest that there is an absolute requirement for a combined level of these two homologous coactivators to allow normal animal development.

Because both coactivators and corepressors may occupy limiting quantities of components of the coactivator or corepressor complex that are essential for the positive or negative activity of a certain nuclear receptor, increasing their levels may respectively lead to squelching or potentiating the activity of this receptor, behaving thus paradoxically and antithetically, as corepressors or coactivators (20). Thus, the qualitative and quantitative mix of coactivators and corepressors in a cell can increase or decrease the sensitivity of this cell to one or more steroids and other nuclear hormones. A change in this mix could lead to hypersensitivity and/or resistance to steroid hormones with hormonal and/or tissue predilection.

The clinical and/or biochemical manifestations of the New World nonhuman primate syndrome and the human multiple steroid resistance syndrome described in this issue (Table 1Go) can both be explained by a defect of a not necessarily the same coregulator molecule. A major difference between the two is the fact that the former is a physiological evolutionary quantitative trait associated with multiple appropriate adaptations, whereas the latter is a pathological syndrome with adverse clinical manifestations. Also, the former includes resistance to all steroid hormones and vitamin D, whereas the latter has clear manifestations of glucocorticoid, mineralocorticoid, androgen and estrogen resistance, and possibly, albeit not yet definitely, progesterone resistance, but no Vitamin D resistance.

The index case of the human syndrome could have been diagnosed with only isolated generalized glucocorticoid resistance on the basis of the clinical and biochemical findings (21). Yet, the physicians were alerted by the paradoxical absence of hyperandrogenic manifestations to pursue the evaluation further. Her mineralocorticoid and mild estrogen resistance could have been missed entirely were it not for the informed diagnostic persistence of the clinicians. The advanced bone age was most likely the result of the different impact of the putative defective coregulator on the cells of the growth plate, where apparently the elevated adrenal androgens were allowed to exert their effects. The absence of a high-circulating aldosterone, estradiol, and progesterone concentration may be due to, respectively, adequate effects of the elevated nonaldosterone adrenal mineralocorticoids on the kidney mineralocorticoid receptor (resulting in excessive salt retention and potassium loss) or estrogen and/or progesterone resistance limited to the uterus and not extended to the hypothalamic-pituitary unit. The milder form of multiple steroid resistance observed in the sister of the proposita could be due to variable penetrance of a similar defect, possibly as a result of genetic background differences in genes with epistatic effects on the functions affected. The absence of overt clinical or biochemical pathology in the parents of the affected sisters could be due to an adequately compensated heterozygotic defect.

The New World primate physiological and biochemical syndrome and the two pathological human multiple steroid resistance syndrome cases described by New et al. (5) are the first states in which a defective steroid receptor coregulator was suggested to be responsible for the clinical and/or biochemical picture (4, 5). Although many attempts have been made to explain the first by imputing steroid receptor binding inhibitory factors in the cytosol, increases in antagonistic steroid receptor isoforms, or presence of hormone-responsive element inhibitors, none of these have been universal to all affected steroid/sterol receptor systems and, thus, cannot explain the entire syndrome in a satisfactory fashion. The likelihood that a coregulator is affected in multiple steroid resistance is high, and the search for altered coregulators should continue in the nonhuman primates and the patients.

The Rubinstein-Taybi syndrome is a good example of a coregulator disease, however, its primary manifestations are not related to the steroid/sterol hormone signal transduction systems (22). On the other hand, the presence of amplification of SRC-3 in certain human breast and ovarian cancers suggests that this coactivator might be responsible for excessive tumor growth, through hypersensitization of the estrogen receptor signal transduction pathway (23). In this instance, a clonal somatic mutation of the coactivator or of one of its regulatory molecules may have led to breast or ovarian tumorigenesis, even though the systemic secretion of estrogen may have been entirely normal in the affected patients. Another imputed human glucocorticoid hypersensitivity state due to steroid coactivator hyperfunction is systemic infection with HIV-1, characterized by profound immunosuppression with a shift of the T cell helper (h) phenotype from Th1 to Th2, as well as by myopathy and muscle atrophy, both known effects of glucocorticoid excess (24). It has been suggested that Vpr, an accessory HIV-1 protein, may be in part responsible for these manifestations by interacting with glucocorticoid receptors, host coactivators and TAF, and by exerting marked glucocorticoid coactivator activity in the immune system and muscle (Table 2Go).

Now that physicians have been alerted to the pathogenic potential of altered coregulators, it is quite likely that more steroid hormone-related syndromes with diverse, albeit logically explained, clinical pictures will be discovered. Some of these syndromes will be admittedly rare, but others may be subtle and common. A good place to start searching for alterations of steroid receptor coregulator molecules is in already recognized syndromes of steroid hormone resistance or hypersensitivity, in which the pathogenicity of the steroid receptor and other known noncoregulator postreceptor steps have been excluded. Importantly, however, the coregulators of steroid hormones should be examined as potential participants in the pathogenesis of common polygenic disorders, such as obesity and the insulin-resistance (visceral fat) syndrome, the polycystic ovary syndrome, hypertension, major depression, autoimmune disorders, infertility, and so on, in which the glucocorticoid, mineralocorticoid and sex steroid signal transduction systems may be pathophysiologically involved (25, 26).


    Footnotes
 
LBD, Ligand-binding domain; DBD, DNA-binding domain; NTD, amino-terminal domain; AF1 or tau1, {tau}1, transactivation function 1; AF2 or tau2, {tau}2, transactivation function 2; NLS1, nuclear localization sequence 1; NLS2, nuclear localization sequence 2; CREB, cyclic AMP-responsive element-binding protein; Jak, Janus protein kinase; STAT, signal transducer and activator of transcription; SRA, steroid receptor activator; CBP, CREB-binding protein; PCAF, p300 and CBP-associated factor; HAT, histone acetylase; HDAC, histone deacetylase; TAFs, transcription associated factors; SRC, steroid receptor coactivator; N-CoR, nuclear receptor corepressor; SMRT, silencing mediator for retinoid and thyroid hormone action.

Received May 12, 1999.

Accepted May 21, 1999.


    References
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