Hormones signal generation
المؤلف:
Peter J. Kennelly, Kathleen M. Botham, Owen P. McGuinness, Victor W. Rodwell, P. Anthony Weil
المصدر:
Harpers Illustrated Biochemistry
الجزء والصفحة:
32nd edition.p509-510
2025-11-27
68
The Ligand-Receptor Complex Is the Signal for Group I Hormones The lipophilic group I hormones diffuse through the plasma membrane of all cells but only encounter their specific, high affinity intracellular receptors in target cells. These receptors can be located in the cytoplasm or in the nucleus of target cells. The hormone-receptor complex first undergoes an activation reaction. As shown in Figure 1, receptor activation occurs by at least two mechanisms. For example, glucocorticoids diffuse across the plasma membrane and encounter their cognate receptor in the cytoplasm of target cells. Ligand-receptor binding results in a conformational change in the receptor leading to the dissociation of the heat shock protein 90 (hsp90 chaperone). This step is necessary for subsequent nuclear translocation of the glucocorticoid receptor (GR). The GR receptor also contains a nuclear localization sequence (NLS) that is now free to facilitate translocation from cytoplasm to nucleus. The activated receptor moves into the nucleus (Figure 1) and binds with high affinity to a specific DNA sequence called the hormone response element (HRE). In the case of the GR, this is a glucocorticoid response element, or GRE. Consensus sequences for various HREs are shown in Table 1. The liganded DNA-bound receptor serves as a high-affinity binding target for one or more transcriptional coactivator proteins, and accelerated gene transcription typically ensues when this occurs. By contrast, certain hormones such as the thyroid hormones and retinoids diffuse from the extracellular fluid across the plasma membrane and go directly into the nucleus. In this case, the cognate receptor is already bound to the HRE (the thyroid hormone response element [TRE], in this example). However, this DNA bound receptor fails to activate transcription because it exists in complex with a corepressor. Indeed, this receptor-corepressor complex serves as a tonic repressor of gene transcription. Association of ligand with these receptors results in dissociation of the corepressor(s). The liganded receptor is now capable of binding one or more coactivators with high affinity, resulting in the recruitment of RNA polymerase II and the GTFs and activation of gene transcription as noted earlier for the GR-GRE complex. The relationship of hormone receptors to other nuclear receptors and to coregulators is discussed in more detail later.
Fig1. Regulation of gene expression by two different group I hormones, thyroid hormone and glucocorticoids. The hydrophobic steroid hormones readily gain access to the cytoplasmic compartment of target cells by diffusion through the plasma mem brane. Glucocorticoid hormones (solid triangles) encounter their cognate receptor, the glucocorticoid receptor (GR) in the cytoplasm where GR exists in a complex with a chaperone protein, heat shock protein 90 (hsp). Ligand binding causes dissociation of hsp90 and a conformational change of the receptor. The receptor-ligand com plex then traverses the nuclear membrane and binds to DNA with specificity and high affinity at a glucocorticoid response element (GRE). This event affects the architecture of a number of transcription coregulators (green triangles), and enhanced transcription ensues. By contrast, thyroid hormones and retinoic acid (black circle) directly enter the nucleus, where their cognate heterodimeric (TR-RXR) receptors are already bound to the appropriate response elements with an associated transcription corepressor com plex (red circles). Binding of hormones occurs, which again induces conformational changes in the receptor leading to dissociation of the corepressor complex from the receptor, thereby allowing an activator complex, consisting of the TR-TRE and coactivator, to assemble. The gene is then actively transcribed.
Table1. The DNA Sequences of Several Hormone Response Elements (HREs)a
By selectively affecting gene transcription and the consequent production of appropriate target mRNAs, the amounts of specific proteins are changed and metabolic processes are influenced. The influence of each of these hormones is quite specific; generally, a given hormone directly affects less than 1% of the genes, mRNA, or proteins in a target cell; sometimes only a few genes are affected. The nuclear actions of steroid, thyroid, and retinoid hormones are quite well defined. Most evidence suggests that these hormones exert their dominant effect on modulating gene transcription, but they—and many of the hormones in the other classes discussed later—can act at any step of the “information pathway,” as illustrated in Figure 2, to control specific gene expression and, ultimately, a biologic response. Direct actions of steroids in the cytoplasm and on various organelles and membranes have also been described. Recently, microRNAs and lncRNAs have been implicated in mediating some of the diverse actions of hormones.
Fig2. The “information pathway. ”Information flows from the gene to the primary transcript to mRNA to protein. Hormones can affect any of the steps involved and can affect the rates of processing, degradation, or modification of the various products.
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