Regulation of gene transcription by hormones

The cDNAs for the glucocorticoid and the oestrogen receptors were isolated more than 15 years ago. They were among the first genes, coding for transcriptional gene activators, to be identified. The family of nuclear receptors is the largest family of transcription factors. Until now, more than 150 different members of the superfamily of nuclear receptors, from worms to insects to humans, have been described. The discovery of an insect receptor for a steroid hormone, ecdysone, indicated that this kind of receptor must have evolved prior to the separation of vertebrates and invertebrates. 

Nuclear receptors are distinguished on the basis of their structural properties, whether they are monomers, homo- or heterodimers, and with respect to the kind of DNA sequences they recognize. Based on these criteria, the nuclear receptor superfamily can be divided broadly into four classes as shown in Table 11.1  

Class I receptors are homodimers. Dimerization is ligand-induced and these receptors bind to DNA half-sites with inverted, palindromic repeats. 

II Thyroid receptor (TR) Heterodimer Tniodothyronine. thyroxin Direct repeat 

III 9-cis-retinoic acid receptor (RxR) Homodimer 9-c/s retinoic acid Direct repeat 

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A comparison of several different steroid receptors with thyroid hormone receptors revealed a remarkable conservation of the amino acid sequence in certain regions, particularly in the DNA-binding domains. This led to the realization that receptors of the steroid or thyroid type are members of a large superfamily of nuclear receptors. Many related members of this family have no known ligand at present and thus are called orphan receptors. The nuclear receptor superfamily plays a critical role in the regulation of gene transcription by hormones, as described in Chapter 43. 

Glass, C. K, Lipkin, S. M., Devary, 0. V, and Rosenfeld, M. G. (1989). Positive and negative regulation of gene transcription by a retinoic acid-thyroid hormone receptor heterodimer, Cell 59, 697-708,... 

Most of the intracellular receptors reside principally in the nucleus, and some of these are constitutively bound, as dimers, to their response element in DNA (e.g., the thyroid hormone receptor). Binding of the hormone changes its activity and its ability to associate with, or disassociate from, DNA. Regulation of gene transcription by these receptors is described in Chapter 16. 

Changes in the phosphorylation state of proteins that bind to cAMP response elements (CREs) in the promoter region of genes contribute to the regulation of gene transcription by a number of cAMP-coupled hormones (see Chapter 16). For instance, cAMP response element binding protein (CREB) is directly phosphory-lated by protein kinase A, a step essential for the initiation of transcription. Phosphorylation at other sites on CREB, by a variety of kinases, also may play a role in regnlating transcription. 

Tsai, M.-J. O Malley, B.W. (1991). Mechanisms of regulation of gene transcription by steroid receptors. In The Hormonal Control Regulation of Gene Transcription, ed. P. Cohen J.G. Foulkes, pp. 101-16. Amsterdam Elsevier. 

Fig. 4 Co-activator and co-repressor complexes are required for nuclear hormone receptor-mediated transcriptional regulation. The tissue-selective fine-tuning of gene transcription by nuclear hormone receptors is due to different co-regulatory complexes that have various functions and enzymatic activities. Co-activator complexes include factors that contain ATP-dependent chromatin remodelling activity often associated with histone acetyltransferase (HAT) activity. Co-repressors include ATP-dependent chromatin remodelling complexes, which function as platforms for the recruitment of several subcomplexes that often contain histone deacetylase (HDAC) activity...

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