Abstract

Molecular Biology of Steroid and Nuclear Hormone Receptors (L. P. Freedman (ed.), Progress in Gene Expression, M. Karin (series ed.) Birkhauser, Boston-Basel-Berlin (1997) 319 p.)

A. N. Smirnov

School of Biology, Lomonosov Moscow State University, Moscow, 119899 Russia; fax: (095) 939-4309

Received December 8, 1998

Explosive expansion of investigations in the field of hormonal signal transduction is rapidly breaking the dogmas of classic endocrinology. The reviewed book confirms this phenomenon in relation to regulators acting via intracellular receptors. Steroid hormone receptors, which have already been known for three decades, have been found to be only a minor part of the superfamily of similarly organized transcription factors whose activity is controlled also by some other hormones (thyroid hormones, retinoic acids, 1,25-dihydroxy vitamin D₃) and several non-hormonal metabolites (derivatives of fatty acids and cholesterol). Ligands for the majority of nuclear receptors have not yet been established (a group of so-called orphan receptors). These receptors are related to each other not only by similarity in their structural/functional organization, but also by their close interactions during signal transduction at several levels, including competition for common ligands (in the case of closely related receptors), competition for identical or overlapping DNA sequences (hormone-responsive elements, though in the case of orphan receptors the prefix «hormone-» is obviously irrelevant), competition for common co-activators and co-repressors (factors of transcription which functionally conjunct nuclear receptors to basic transcriptional machinery), as well as forming of heterodimeric receptor complexes with dual regulation and new DNA target sequences. Thus, nuclear receptors mediate signals of ligands of different nature (not only hormonal) and, possibly, signals that do not include a ligand moiety. In this context, the statement of one of the authors, B. M. Forman, that «nuclear receptors ... pave the way toward a new endocrinology» (p. 298) appears to be quite true. The book serves as a summary of the development of science in the field of structural/functional organization of nuclear receptors for the last 8 to 10 years and represents a collected volume of 11 reviews written by leading specialists of the art.

The steroid hormone receptors form a subfamily of proteins, one of their peculiarities being the ability to interact with chaperon proteins of the group of heat shock proteins (Hsp). In chapter 1, «The role of heat-shock proteins in the regulation of steroid receptor function» (D. Picard), a model for the ordered process of oligomeric receptor complex assembly that includes, according to modern findings, up to 8 proteins, is presented, and possible functions of chaperons are analyzed. Unlike other receptors of the superfamily, steroid receptors are found both in the cell nucleus and cytoplasm. In chapter 2, «Subcellular and subnuclear trafficking of steroid receptors» (D. B. DeFranco), possible mechanisms determining the equilibrium between two receptor forms are considered. One should admit that this aspect of receptor dynamics is one of the least elaborated. Chapter 3, "Structure and function of the steroid and nuclear receptor ligand binding domain” (S. S. Simons), is a fundamental review on the structure and functions of the ligand binding domain of receptors which contains sequences determining, apart from ligand binding, also the ability of the receptor to interact with Hsp90, dimerization, nuclear translocation, and co-activator and co-repressor binding. Data showing conformational mobility of this domain, which determines peculiarities of biological activities of hormonal agonists and antagonists, are considered. Chapter 4, "Structure and function of the steroid and nuclear receptor DNA binding domain” (F. Rastinejad), contains detailed analysis of the physicochemistry of receptor recognition of hormone responsive elements in DNA. These elements are include two types of sequences organized as palindromes or direct repeats. When receptor heterodimers bind to direct repeats, the hinge region of one of the partners was shown to act as a molecular ruler that measures the size of the spacer between two half sites of the hormone responsive element. The DNA binding domain is constructed from two modules, the form of "zinc fingers” playing different functions in DNA recognition. The results are based in particular on X-ray data and represent the most elaborated aspect of receptor activities. Chapter 5, "Modulation of steroid/nuclear receptor dimerization and DNA binding by ligands” (B. Cheskis, L. Freedman), contains findings on receptor dimerization in solution and on the DNA matrix. In the first case regions of the ligand binding domain are involved, while in the second case regions of the DNA binding domain also participate. The resulting cooperativity stabilizes the triple complex. A number of anti-hormones induce excessive stability of such complexes, thereby blocking the scanning of DNA by the receptor and its action by the "hit and run” rule. A particular situation takes place with ligand effects on receptor heterodimerization. The inverse influence of dimerization of receptors on their affinity for ligands is also considered. In chapter 6, "Molecular mechanisms of nuclear receptor-mediated transcriptional activation and basal repression” (M. K. Bagchi), findings on hormone-dependent interactions between receptors and basic transcriptional factors of promoters containing the TATA element and recently revealed protein factors (co-activators and co-repressors) which act as bridges between receptors and basal transcriptional factors or as stabilizers of their direct interactions with receptors are presented. The main accent in these investigations is on activation function 2 of the C-terminal receptor region, while activation function 1 of the N-terminal region remains insufficiently highlighted. Chapter 7, "Transcriptional cross-talk by steroid hormone receptors” (P. Herrlish, M. Gottlicher) concerns mainly putative mechanisms of negative effects of steroid hormones on transcription. In particular, these effects relate to promoters regulated by factors AP-1 and NFkB and which do not contain full-value hormone responsive elements. In chapter 8, "Chromatin and steroid-receptor-mediated transcription” (C. E. Watson, T. K. Archer), the influence of nucleosome positioning with respect to hormone responsive elements on the efficacy of various hormone effects and hormone-induced changes in chromatin structure reflected in the appearance of DNA sites with hypersensitivity for nucleases are considered. Chromatin remodeling is proposed to be a prerequisite but not sufficient stage in hormone receptor action. Chapter 9, "Regulation of glucocorticoid and estrogen receptor activity by phosphorylation” (M. J. Garabedian et al.), is devoted to a long-studied aspect of inter-signal interactions. Phosphorylated amino acid residues are localized mainly in the N-terminal region of receptors and serve as targets for various protein kinases. The influence of phosphorylation on hormone-binding and other receptor functions is considered. In chapter 10, "Monomeric nuclear receptors” (M. A. Lazar, H. P. Harding), the effects and interaction with DNA of orphan and thyroid hormone receptors which act via DNA responsive elements present as half sites are considered. Such elements at their 5´-terminals contain extensions of 2 to 4 bp specifically recognized by the receptor hinge region. Chapter 11, "Orphan nuclear receptors and their ligands” (B. M. Forman), is devoted to the methodology for revealing of regulatory ligands which are usual products of metabolism of nutritional substances. The most probable natural ligands of retinoid RXR receptors are phytenic and 9-cis-retinoic acids; those of peroxisome proliferation activator receptors (PPAR) are 15-deoxy-Delta^12,14-prostaglandin J₂ (for PPARgamma), linoleic acid (for PPARdelta), 8S-hydroxyeicosatetraenoic acid (for PPARalpha); that of liver-specific receptor LXR is 24(S),25-epoxycholesterol; and that of farnesoid receptor X (FXR) is farnesol. Findings on receptor expression and consequences of its blockage are also presented.

The book is of clear interest for endocrinologists, biochemists, and molecular biologists. The discussion of orphan receptors and their cognate ligands should also attract the attention of specialists on nutrition and the correction of metabolic processes.