Inhibition of transcription is usually achieved by the interaction of the receptor with corepressors [ ]. Both proteins have several isoforms. Other proteins, such as the small ubiquitous nuclear corepressor SUN-CoR and the Alien protein, might also serve as nuclear hormone receptor corepressors [ , ]. They also bind to other proteins, including HDACs [ , ]. Recent developments identified a heterogeneous group of corepressors of a new type.
What makes them unique among corepressors is the fact that they bind to the receptor activated by the hormone. The preferentially expressed antigen in melanoma PRAME is expressed in various cancers, but in healthy tissues it is present only in testes, ovaries, endometrium, and adrenal glands. It likely executes this inhibition by recruiting other corepressors [ ]. By doing so in the presence of agonist, it inhibits the activity of target gene, while in the presence of antagonist it magnifies its action [ ]. Metastasis-associated factor 1 MTA1 is another corepressor preferentially binding to a ligand-activated ER [ ].
It inhibits the expression of estrogen target genes by competing with coactivators for the binding to the receptor, by recruiting HDAC, and by chromatin modification. A group of corepressors that might bind both liganded and nonliganded hormone receptors is also known. Natural HREs are located relatively close to TSS or in more distant regulatory elements, and binding sites for other transcription factors are usually located nearby.
Such proximity permits interaction between nuclear receptors and these transcription factors, leading either to the suppression of gene activity as described above or to its additive or synergistic activation. The binding of nuclear receptors to other transcription factors might also occur in a DNA-binding-independent manner.
Their N-terminal ends tails protrude from the compact nucleosome body. Epigenetic modifications of amino acids forming such tails play a marked role in chromatin organization. Increased acetylation relieves compact chromatin, which results in an exposure of the transcription-factor-binding sites and their increased accessibility leading to transcription activation. On the other hand, deacetylation of histone tails leads to the formation of a compact chromatin. As a result, transcription-factor-binding sites become inaccessible to transactivators, and the gene becomes transcriptionally inactive.
Such a mechanism of modification of chromatin structure is utilized by nuclear hormone receptors, which, as mentioned above, interact with coactivators and corepressors. The binding of a ligand-activated receptor to HRE initiates the formation of a coactivator complex, which, thanks to the HAT activity, increases histone acetylation and induces local decondensation of chromatin Figure 5 a. On the other hand, the binding of a hormone-free receptor to HRE initiates the formation of a corepressor complex, which, thanks to its HDAC activity, induces local condensation of chromatin Figure 5 b.
Finally, the corepressor complex and its HDAC activity are utilized by the specific corepressor proteins described above, which bind to a hormone-activated receptor and inhibit transcription of the target gene Figure 5 c. Fast biological effects of hormones, just seconds or minutes after hormone administration, have already been described several dozen years ago. The rapidity of biological response and its independence from transcription and from translation suggested that the genomic mechanism of hormone action is not involved; therefore, this mechanism was called nongenomic or extragenomic.
The nongenomic mechanisms of hormone action are multiple, variable, and only partially known Figure 6. Simplified diagram of nongenomic mechanisms of action of small-molecule hormones. All nongenomic mechanisms activate numerous transduction pathways, and, by a series of phosphorylation events of cytoplasmic and of nuclear proteins, modify cell function. A Interaction of the hormone with either cell membrane receptor or directly with membrane phospholipids modifies the function of ion channels.
B Activation of phospholipase C initiated by the hormone-activated cell membrane receptor, and of adenylate cyclase and, most possibly, of other enzymes stimulates production of secondary messengers. C Activation of c-SRC by the hormone-activated nuclear receptor. E In mitochondria, small-molecule hormones acting via their nuclear receptors or by their shorter mitochondrial isoforms regulate transcription of mitochondrial DNA.
In addition, interaction of some hormones alone or of hormone-receptor complexes with mitochondrial proteins stimulates thermogenesis. F The binding of the hormone activates protein kinase. Steroid and nonsteroid small-molecule hormones bind to various proteins localized outside the nucleus and activate transduction pathways leading to a fast biological response. The presence of binding sites in the cell membrane was proved for all major representatives of these hormones; however, in many cases the identity of the binding protein remains unknown.
In addition, it is likely that such hormones have more than one type of membrane receptors. In the case of receptors already identified, their mode of action is by and large only partially resolved. It is then plausible that nuclear receptors of other small-molecule hormones are present close to or in the cell membrane.
Some small-molecule hormones bind to other than nuclear receptor-like cell membrane proteins. The G-protein-interacting cell membrane receptor for steroid-hormone-binding protein SHBG binds androgens with higher and estrogens with lower affinity. The prerequisite for signal transduction from the hormone to the cell interior by this receptor is the binding of a hormone-free SHBG first, followed by hormone binding [ , ].
Small-Molecule Hormones: Molecular Mechanisms of Action
The best studied is membrane targeting of ER. It is induced by palmitoylation of cysteine [ ], a modification increasing protein hydrophobicity and, therefore, facilitating protein association with lipid bilayer. Binding to caveolins is required for membrane localization of the receptor [ ].
Furthermore, binding to caveolins allows hormone receptors to initiate fast, specific nongenomic response to hormonal stimulus. Upon binding to the cell membrane receptors, small-molecule hormones activate various transduction pathways by a receptor-type-dependent mechanism. As a result, activated kinases phosphorylate and activate numerous cytoplasmic and nuclear proteins, including hormonal receptors, transcription factors and coactivators. This, in turn, modulates various biological processes in the cytoplasm and influences transcription of genes regulated by newly phosphorylated hormone receptors and transcription factors.
Cell-membrane-located small-molecule hormone receptors interacting with G proteins might also activate adenylate cyclase, which results in the generation of yet another secondary messenger, cAMP, and in the activation of cAMP-dependent proteins, such as PKA, and of their substrates [ — ]. Small-molecule hormones also bind to the proteins present in the cytoplasm; commonly, such proteins are cytoplasmic fractions of nuclear receptors.
Activated kinase increases production of IP3 which, in turn, activates the mitogen-activated protein kinase MAPK pathway [ — ]. Of note is nuclear hormone receptors' binding to CaM, being an example of cross-talking of hormonal signaling with other signal transduction pathways. It results in the increased stability of the receptor due to CaM-dependent protection from degradation [ 85 — 87 ]. The binding profoundly affects receptor function: Small-molecule hormones could also bind to another, nonreceptor type cytoplasmic proteins. Small-molecule hormones modulate the function of mitochondria by a number of mechanisms.
One of them is based on the action of their nuclear receptors as transcription factors. Each mitochondrion has multiple copies of its own DNA mtDNA encoding 37 genes, including genes for 13 proteins involved in oxidative phosphorylation. Another mechanism of small-molecule hormones action in mitochondria is based on their interactions with other proteins. For example, diiodothyronine T2 binds to the Va subunit of cytochrome c oxidase and activates this enzyme [ ]. Adenine nucleotide translocase ANT binds all- trans -retinoic acid [ ].
Orphan nuclear receptor Nur77 mediates apoptosis by interaction with Bcl-2 and by induction of cytochrome c release [ ]. Finally, hormonal receptors can directly bind to mitochondrial membranes and modify membrane potential, as shown, for example, for stress-activated GR [ ]. Such a mechanism was described for mRNA encoding neuronal GluR1 protein, a subunit of the glutaminergic receptor. The binding of all- trans -retinoic acid induces the change of receptor conformation and decreases its affinity for mRNA; as a result the receptor dissociates from mRNA [ ].
A very rapid effects of androgens, progesterone, glucocorticoids, and other steroid hormones, evident just a few seconds after hormone administration, might be a result of a nonspecific, nongenomic mechanism of small-molecule hormones action, based on their interactions with lipid bilayers. Lipophilic steroid hormone molecules could directly bind to membrane phospholipids and, by doing so, modulate their function.
This, in turn, influences the function of membrane proteins such as the calcium pump and other channel proteins, leading to an immediate transport modification of various ions. Nonspecific binding of steroid hormones to a mitochondrial membrane might increase proton leak [ , ]. Medical conditions associated with out-of-range level of small-molecule hormones are known for decades, relatively common, and have been exhaustively described in numerous handbooks and articles.
In contrast, much less is known about diseases initiated by abnormalities of the receptor. They are uncommon, with a wide range of signs and symptoms of variable severity related to both the type and site of genetic error within the receptor-encoding gene or related genes that might mimic signs and symptoms of other diseases e. Detailed description of these diseases exceeds the scope of this paper; however, in Table 2 the reader can find a comprehensive summary and references to the review and original articles regarding selected human hormone-receptor-related pathologies.
Hormone-receptor-related diseases constitute an important diagnostic challenge. Among them, a monogenic diseases arising due to mutation are the easiest to diagnose, provided that a candidate gene is identified and its sequencing shows mutation. It is much more difficult, though, to evaluate the influence of altered expression or function e. However, the importance of such dysfunctions in pathophysiology of both rare and common diseases fully justifies the efforts to elucidate the molecular mechanisms of action of these receptors.
Importantly, identification of these mechanisms is crucial for designing new targeted therapeutic strategies. Small-molecule hormones, usually of quite simple chemical structure, have an enormously wide range of biological functions. The effects of their action are due to their interaction with various receptors, which, by further interaction with other proteins or with DNA, activate various signal transduction pathways or regulate the activity of numerous target genes.
Quantification of the Vitamin D Receptor - Coregulator Interaction
Even though our knowledge regarding these nongenomic and genomic mechanisms is already impressive, a lot of information regarding, first of all, their interdependence still awaits elucidation. National Center for Biotechnology Information , U. Journal List Int J Endocrinol v. Published online Feb This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Small-molecule hormones play crucial roles in the development and in the maintenance of an adult mammalian organism.
Introduction Molecular mechanisms of action of small-molecule hormones have been studied for decades. Open in a separate window. Table 1 Selected representatives of the nuclear receptor superfamily. Hormone Response Elements in the Promoters of Target Genes A classic, genomic mechanism of action of small-molecule hormones is based on the binding of its nuclear receptor to the target gene.
Regulation of Transcription On the basis of the molecular mechanism of action and of the subcellular localization in the absence of ligand, nuclear hormone receptors can be divided into two types. Type I Receptors In the circulation, steroid hormones are bound to transporting proteins. Type II Receptors Families I and II receptor proteins, synthesized and modified in the cytoplasm, have their NLS exposed so they can translocate to the nucleus in the absence of the hormone.
Interaction of Nuclear Hormone Receptors with Other Proteins As mentioned above, the biological action of small-molecule hormones depends on their interaction with their receptors, as well as on the interactions of the receptor with DNA and with other proteins. The Nongenomic Mechanisms of Action of Small-Molecule Hormones Fast biological effects of hormones, just seconds or minutes after hormone administration, have already been described several dozen years ago.
Nongenomic Mechanisms of Hormone Action Induced by the Interaction of Hormones with Membrane and Cytoplasmic Receptors Steroid and nonsteroid small-molecule hormones bind to various proteins localized outside the nucleus and activate transduction pathways leading to a fast biological response. Induction of Transduction Pathways Upon binding to the cell membrane receptors, small-molecule hormones activate various transduction pathways by a receptor-type-dependent mechanism. Nuclear Hormone Receptor Binding to Calmodulin Of note is nuclear hormone receptors' binding to CaM, being an example of cross-talking of hormonal signaling with other signal transduction pathways.
Hormone Binding to Nonreceptor Proteins Small-molecule hormones could also bind to another, nonreceptor type cytoplasmic proteins. Small-Molecule Hormones Action in Mitochondria Small-molecule hormones modulate the function of mitochondria by a number of mechanisms. Direct Interaction of Small-Molecule Hormones with Membranes A very rapid effects of androgens, progesterone, glucocorticoids, and other steroid hormones, evident just a few seconds after hormone administration, might be a result of a nonspecific, nongenomic mechanism of small-molecule hormones action, based on their interactions with lipid bilayers.
Human Pathologies Associated with Receptor Abnormalities Medical conditions associated with out-of-range level of small-molecule hormones are known for decades, relatively common, and have been exhaustively described in numerous handbooks and articles. Table 2 Selected human pathologies associated with hormone receptors. Conclusion Small-molecule hormones, usually of quite simple chemical structure, have an enormously wide range of biological functions. Pituitary resistance to thyroid hormones: Homozygous thyroid hormone receptor b gene mutations in resistance to thyroid hormone: Journal of Clinical Endocrinology and Metabolism.
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Journal of Proteome Research. Androgen receptor serine 81 phosphorylation mediates chromatin binding and transcriptional activation. Proteasome-mediated glucocorticoid receptor degradation restricts transcriptional signaling by glucocorticoids. Sengupta S, Wasylyk B. Ligand-dependent interaction of the glucocorticoid receptor with p53 enhances their degradation by Hdm2.
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Glucocorticoid receptor transcriptional activity determined by spacing of receptor and nonreceptor DNA sites. Description First published in , Vitamins and Hormones is the longest-running serial published by Academic Press. In the early days of the Serial, the subjects of vitamins and hormones were quite distinct. The Editorial Board now reflects expertise in the field of hormone action, vitamin action, X-ray crystal structure, physiology, and enzyme mechanisms.
Under the capable and qualified editorial leadership of Dr. Gerald Litwack, Vitamins and Hormones continues to publish cutting-edge reviews of interest to endocrinologists, biochemists, nutritionists, pharmacologists, cell biologists, and molecular biologists. Others interested in the structure and function of biologically active molecules like hormones and vitamins will, as always, turn to this series for comprehensive reviews by leading contributors to this and related disciplines. Product details Format Hardback pages Dimensions Dirty Genes Ben Lynch.
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