Comparison between synthetic nuclear localization signal peptides from the steroid/thyroid hormone receptors superfamily (original) (raw)
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Effect of DNA on Thyroid-Hormone Binding by Specific Receptor Proteins from Rat-Liver Nuclei
European Journal of Biochemistry, 1981
Influence of double-stranded native DNA on the binding of thyroid hormone, 3,5,3'-triiodo-~-thyronine, by the isolated nuclear receptors was studied and the following results were obtained. (1) The receptor-triiodothyronine complexes bound to DNA with moderate affinities. (2) DNA enhanced the hormone binding of the receptors. The stimulatory DNA effect on triiodothyronine binding of the receptors was dependent on DNA concentration, showing its maximum at 30 pg/ml. (4) The increase in triiodothyronine binding was observed not only in the initial velocity but also in the plateau level which was attained after sufficient incubation time.
Genetic Engineering, 1990
The nuclear receptor superfamily comprises a large group of proteins with functions essential for cell signaling, survival, and proliferation. There are multiple distinctions between nuclear superfamily classes defined by hallmark differences in function, ligand binding, tissue specificity, and DNA binding. In this review, we utilize the initial classification system, which defines subfamilies based on structure and functional difference. The defining feature of the nuclear receptor superfamily is that these proteins function as transcription factors. The loss of transcriptional regulation or gain of functioning of these receptors is a hallmark in numerous diseases. For example, in prostate cancer, the androgen receptor is a primary target for current prostate cancer therapies. Targeted cancer therapies for nuclear hormone receptors have been more feasible to develop than others due to the ligand availability and cell permeability of hormones. To better target these receptors, it is critical to understand their structural and functional regulation. Given that late-stage cancers often develop hormone insensitivity, we will explore the strengths and pitfalls of targeting other transcription factors outside of the nuclear receptor superfamily such as the signal transducer and activator of transcription (STAT).
Cell regulation, 1990
The glucocorticoid receptor accumulates in nuclei only in the presence of bound hormone, whereas the estrogen receptor has been reported to be constitutively nuclear. To investigate this distinction, we compared the nuclear localization domains of the two receptors and the capacity of their respective hormone-binding regions to regulate nuclear localization activity. As with the glucocorticoid receptor, we showed that the human estrogen receptor contained a nuclear localization signal between the DNA-binding and hormone-binding regions (amino acids 256-303); however, in contrast to the glucocorticoid receptor, the estrogen receptor lacked a second nuclear localization domain within the hormone-binding region. Moreover, the hormone-binding domain of the unliganded estrogen receptor failed to regulate nuclear localization signals, although it efficiently regulated other receptor functions. We conclude that the two receptors employ a common mechanism for signal transduction involving a novel "inactivation" function, but that they differ in their control of nuclear localization. Thus, despite the strong relatedness of the estrogen and glucocorticoid receptors in structure and activity, certain differences in their properties could have important functional implications.
Intranuclear trafficking and gene targeting by members of the steroid/nuclear receptor superfamily
The Journal of Steroid Biochemistry and Molecular Biology, 1998
Upon binding to regulatory elements in mammalian chromosomes, steroid receptors induce speci®c transitions in the nucleoprotein structure of the template. These transitions re¯ect, in part, the reorganization of chromatin structure to permit interaction of secondary factors with target sequences in promoter regulatory regions. Steroid receptors represent a class of transcriptional activators that are able to interact with repressed nucleoprotein templates and recruit necessary activities for chromatin remodeling. The ligand-induced movement of nuclear receptors from inactive states, either in the cytoplasm or in the nucleus, to productive interactions with chromatin is complex and likely re¯ects the interaction with multiple protein complexes and subcellular structures. Regulation of gene expression by nuclear receptors is thus mediated through the subcellular distribution of inactive receptors, the redistribution of activated receptor complexes to appropriate nuclear domains, the reorganization of chromatin structures for interaction with soluble components of the nucleoplasm, and direct protein±protein contacts between receptors and the basal transcription apparatus.
Ligand-protein interactions in nuclear receptors of hormones
Nuclear hormone receptors are transcription factors regulated by lipophilic ligands. These hormones bind to their nuclear receptor targets using an induced fit mechanism that triggers a large conformational change and generates the proper surface for the binding of protein coactivators. The molecular details of the various steps of this activation process or its inhibition by antagonists are now understood for several nuclear receptors. ß
The Journal of Steroid Biochemistry and Molecular Biology, 1999
Nuclear receptors are ligand-inducible transcription factors which mediate the physiological eects of steroid, thyroid and retinoid hormones. By regulating the assembly of a transcriptional preinitiation complex at the promoter of target genes, they enhance the expression of these genes in response to hormone. Recent evidence suggests that nuclear receptors act in part by recruiting multiple coregulator proteins which may have speci®c functions during transcriptional initiation. Liganded receptors recruit members of the SRC family, a group of structurally and functionally related transcriptional coactivators. Receptors also interact with the transcriptional cointegrators p300 and CBP, which are proposed to integrate diverse aerent signals at hormone-regulated promoters. p300/CBP and members of the SRC coactivator family have intrinsic histone acetyltransferase activity which is believed to disrupt the nucleosomal structure at these promoters. Other nuclear receptor coactivators include a member of the SWI/SNF complex, BRG-1, which couples ATP hydrolysis to chromatin remodelling, and the E3 ubiquitinprotein ligases E6-AP and RPF-1. Finally, nuclear receptor coactivators appear to be organized into preformed subcomplexes, an arrangement that may facilitate their ecient assembly into diverse higher order con®gurations. # Journal of Steroid Biochemistry and Molecular Biology 69 (1999) 3±12 0960-0760/99 $ -see front matter # 1999 Elsevier Science Ltd. All rights reserved. PII: S 0 9 6 0 -0 7 6 0 ( 9 8 ) 0 0 1 4 4 -7
Interactions of exogenous endocrine active substances with nuclear receptors
Pure and Applied Chemistry, 2003
Nuclear receptors function as ligand-regulated transcription factors and modulate the expression of sets of genes in response to varying concentrations of ligands. The ligand modulators can be endogenous metabolites that function as hormones, or they can be exogenous substances, such as pharmaceutical agents or environmental substances of natural or man-made origin, which in some cases can cause endocrine disruption. Ligands modulate nuclear receptor activity by binding to their ligand-binding domains and stabilizing conformations that lead either to transcriptional activation or repression. The ligand-binding pocket is somewhat flexible, and binding affinities can be measured over a 10-million-fold range (i.e., with equilibrium dissociation constant values ranging from ca. 0.01 nM to 100 µM). Thus, it is not surprising that by binding a large variety of structures, some nuclear receptors can appear to be promiscuous; however, when affinity is considered, the binding patterns are more restricted. The spectrum of ligands that bind to the estrogen receptor has been most thoroughly investigated. Those from natural sources include natural products in food, such as soy isoflavones and whole grain lignans, as well as microbial products and components from wood. Aside from pharmaceuticals, man-made estrogen ligands can be found in industrial products, such as alkyl phenols from nonionic detergents, bisphenols from plastics, indicator dye impurities, polymer chemicals, and chlorinated aromatics and pesticides. Exogenous ligands are also known for the androgen and progesterone receptors. While it is possible that endocrine disruption can result from exogenous chemicals acting directly as ligands for the nuclear receptors, endocrine disruption needs to be considered in the broader context; thus, compounds also need to be assessed for their effects at other levels, such as on endogenous hormone production, transport, metabolism, and clearance, and at points in signal transduction cascades that are beyond the ligand-receptor interaction.