A new "new" syndrome in the new world: is multiple postreceptor steroid hormone resistance due to a coregulator defect?

Abstract

I 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 1). 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 1). 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). 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 1). 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) (6–8) (Fig. 1). The latter is quite long and nonhomologous in steroid hormone receptors. It contains a strong independent transactivation domain (AF1 or t1) 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 t2), 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 cjuncfos and nuclear factor (NF)-kB heterodimers. 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 AF1and AF2-interacting, “bridging” nucleoproteins, the coactivators that have chromatin-remodeling and other enzymatic activities (11, 12) (Figs. 1 and 2). The known coactivators of steroid receptors belong to several families (Table 2). The p160 family and the recently described riboprotein coactivator steroid receptor activator (SRA) include members whose activities are limited to nuclear receptors (11–13). 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-NFkB Received May 12, 1999. Accepted May 21, 1999. 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@mail.nih. gov. LBD, Ligand-binding domain; DBD, DNA-binding domain; NTD, amino-terminal domain; AF1 or tau1, t1, transactivation function 1; AF2 or tau2, t2, transactivation function 2; NLS1, nuclear localization sequence 1; NLS2, nuclear localization sequence 2; CREB, cyclic AMPresponsive 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. 0021-972X/99/$03.00/0 Vol. 84, No. 12 The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A. Copyright © 1999 by The Endocrine Society