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Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

NGFI-A is an immediate-early response gene induced by signals that initiate growth and differentiation. Its mRNA encodes a sequence-specific transcriptional activator possibly implicated in the control of brain developmental processes. Due to the essential role of thyroid hormone for a correct brain development, we have now investigated the possible regulation by 3,5,3'-triiodo-L-thyronine (T3) of NGFI-A gene expression during maturation of the central nervous system. Our results indicate that expression of mRNA encoding NGFI-A transcription factor is about 8-fold decreased in the brain of neonatal hypothyroid rats. No changes were seen when hypothyroidism was induced in adult life. T3 treatment increased NGFI-A mRNA within 1 h, suggesting that thyroid hormone effect is likely to be a direct one. These data indicate a strong regulation by thyroid hormone of the expression of the growth factor inducible gene NGFI-A during brain development, making this gene a suitable model to study T3 action in the early developing nervous system.
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PMID:Thyroid hormone up-regulates NGFI-A gene expression in rat brain during development. 137 Apr 44

Gene regulation by thyroid hormones is mediated through multiple nuclear receptors. Only some of these thyroid hormone receptor (TR) isoforms become transcriptional enhancers in the presence of the thyroid hormone T3. Here we analyze the regulatory function of the human TR alpha 2 isoform. This protein does not bind T3 and is not a transcriptional activator of thyroid hormone-responsive elements (TRE). Transfected TR alpha 2 functions as a constitutive repressor of the transcriptional activators TR alpha 1 and TR beta 1 but also represses heterologous receptors, including the retinoic acid receptor and the estrogen receptor, which can activate TRE-controlled genes. TR alpha 2 protein showed strongly reduced DNA binding to a palindromic TRE when compared with the active TRs. Hybrid receptor analysis revealed that the special properties of the TR alpha 2 protein, including its repressor function and DNA binding characteristics, are intrinsic properties of its carboxyterminus and can be transferred to other receptors. Although it has been shown that the active TRs can act as repressors and silencers due to their strong DNA binding in the absence of hormone, our data show that TR alpha 2 is unlikely to inhibit TRs and other receptors through a competitive DNA binding mechanism. Antibody gel shift experiments suggest that repression by TR alpha 2 might result from interaction with active receptors. Thus, the receptor-like TR alpha 2 isoform differs from typical nuclear receptors in its DNA-binding and ligand-binding properties and appears to regulate the activity of other receptors via protein-protein interaction.
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PMID:Regulatory functions of a non-ligand-binding thyroid hormone receptor isoform. 178 15

An in vivo selection system for isolating targets of DNA binding proteins in yeast was developed and used to identify the DNA binding site for the NGFI-B protein, a member of the steroid-thyroid hormone receptor superfamily. The feasibility of the technique was verified by selecting DNA fragments that contained binding sites for GCN4, a well-characterized yeast transcriptional activator. The DNA binding domain of NGFI-B, expressed as part of a LexA-NGFI-B-GAL4 chimeric activator, was then used to isolate a rat genomic DNA fragment that contained an NGFI-B binding site. The NGFI-B response element (NBRE) is similar to but functionally distinct from elements recognized by the estrogen and thyroid hormone receptors and the hormone receptor-like proteins COUP-TF, CF1, and H-2RIIBP. Cotransfection experiments in mammalian cells demonstrated that NGFI-B can activate transcription from the NBRE with or without its putative ligand binding domain.
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PMID:Identification of the DNA binding site for NGFI-B by genetic selection in yeast. 192 41

Thyroid hormone receptors (TRs) are nuclear proteins that regulate gene expression through interactions with specific DNA sequences. It is well known that thyroid hormones have critical functions in the control of normal brain development. In the rat brain, at least three mRNA species are generated by differential processing of the TR alpha transcript. Only one of the isoforms, TR alpha-1, is a transcriptional activator, while the regulatory roles of the carboxy-terminal variants TR alpha-2 and TR alpha-2v remain unclear. In this study we have used polymerase chain reaction amplification of total RNA to compare TR alpha-1, TR alpha-2, and TR alpha-2v mRNA levels in the brainstem, cerebellum, cerebrum, midbrain, and olfactory bulbs of developing neonatal brains in rats. RNA was collected 5, 10, 15, 20, and 25 days after birth from both normal and hypothyroid animals. Coordinate expression of all three isoforms was observed in most tissues during development, with TR alpha-2 generally maintaining the highest level of expression, and TR alpha-1 the lowest. In hypothyroid tissues, TR alpha-1 message was generally increased, while TR alpha-2 was not. To explore the possible roles of the TR alpha isoforms, we have compared their DNA-binding activities. We report that compared to TR alpha-1, the carboxy-terminal variants TR alpha-2 and TR alpha-2v show different binding patterns with a thyroid hormone response element, suggesting that they bind only poorly as monomers. The varying ratios of the TR alpha isoform expression together with their distinct binding patterns and reported repressor functions suggest that TR alpha isoforms have important roles during brain development and function, and may serve to fine-tune the biological responses to thyroid hormone.
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PMID:Coordinate expression of functionally distinct thyroid hormone receptor alpha isoforms during neonatal brain development. 194 7

The human progesterone receptor (PR) is a member of the steroid/thyroid hormone superfamily of nuclear receptors. The receptor is expressed as two forms, PR-B and the shorter PR-A, which lacks the NH2-terminal 164 amino acids of PR-B; whereas PR-B seems to be predominantly a transcriptional activator, PR-A also functions as a repressor. Our previous studies of PR expressed in T47D breast cancer cells have shown that PR is a phosphoprotein whose phosphorylation is enhanced in response to hormone. There is an initial rapid (minutes) increase in phosphorylation followed by a slower, less substantial increase, which results in decreased mobility of the receptor on sodium dodecyl sulfate gels. We now report the identification of three phosphorylation sites, which are predominantly phosphorylated during the later phase of the response to hormone. These sites, Ser102, Ser294, and Ser345, are all found in Ser-Pro consensus sequences. Whereas Ser294 and Ser345 are common to PR-A and PR-B, Ser102 is unique to PR-B. Finally, we demonstrate that phosphorylation of Ser345 is associated with the altered mobility on sodium dodecyl sulfate gels.
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PMID:Identification of a group of Ser-Pro motif hormone-inducible phosphorylation sites in the human progesterone receptor. 747 77

In this study we have investigated the role of the N-terminal region of thyroid hormone receptors (TRs) in thyroid hormone (TH)-dependent transactivation of a thymidine kinase promoter containing TH response elements composed either of a direct repeat or an inverted palindrome. Comparison of rat TR beta 1 with TR beta 2 provides an excellent model since they share identical sequences except for their N termini. Our results show that TR beta 2 is an inefficient TH-dependent transcriptional activator. The degree of transactivation corresponds to that observed for the mutant TR delta N beta 1/2, which contains only those sequences common to TR beta 1 and TR beta 2. Thus, TH-dependent activation appears to be associated with two separate domains. The more important region, however, is embedded in the N-terminal domain. Furthermore, the transactivating property of TR alpha 1 was also localized to the N-terminal domain between amino acids 19 and 30. Using a coimmunoprecipitation assay, we show that the differential interaction of the N terminus of TR beta 1 and TR beta 2 with transcription factor IIB correlates with the TR beta 1 activation function. Hence, our results underscore the importance of the N-terminal region of TRs in TH-dependent transactivation and suggest that a transactivating signal is transmitted to the general transcriptional machinery via a direct interaction of the receptor N-terminal region with transcription factor IIB.
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PMID:The N-terminal region (A/B) of rat thyroid hormone receptors alpha 1, beta 1, but not beta 2 contains a strong thyroid hormone-dependent transactivation function. 753 21

The thyroid hormone (T3) receptors (TRs) are hormone-dependent transcription factors that regulate expression of a variety of specific target genes. To help elucidate the mechanisms that underlie this transcriptional regulation and other potential TR activities, we used the yeast interaction trap to isolate clones encoding proteins that specifically interact with the ligand binding domain of the rat TR beta. Several such proteins, called Trips (TR-interacting proteins), were isolated from independent selections carried out either in the presence or absence of T3. Surprisingly, all of the Trips were dependent on hormone for interaction with the TR, with some interacting only when T3 is present and others only when it is absent. Nearly all of the Trips also show similar ligand-dependent interaction with the retinoid X receptor (RXR), but none interact with the glucocorticoid receptor under any conditions. The sequences of three of the Trips predict specific functional roles: one is an apparent human homolog of a yeast transcriptional coactivator, one is a new member of a class of nonhistone chromosomal proteins, and one contains a conserved domain associated with ubiquitination of specific target proteins. Consistent with the pleiotropic effects of TR and RXR, several other Trips show significant amino acid sequence similarity with proteins involved in various regulatory pathways. The inherent transcriptional activity of the Trips was tested in yeast, and a chimeric protein consisting of a fusion of Trip4 to the bacterial LexA repressor protein is a relatively strong transcriptional activator. Similar LexA fusions to Trip9 and Trip10 had no transcriptional activity on their own but, when coexpressed with both TR and RXR, conferred T3-dependent activation to a reporter gene controlled by LexA binding sites. We suggest that this indirect T3 response provides a novel mechanism for hormonal activation of gene expression, and that studies of the Trips will provide important insights into the specific mechanisms of action of TRs and other receptors.
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PMID:Two classes of proteins dependent on either the presence or absence of thyroid hormone for interaction with the thyroid hormone receptor. 777 74

We report here a characterization of the thyroid hormone receptors (T3Rs), retinoic acid receptors (RARs), and retinoid X receptors (RXRs) by reconstituting their actions in the fission yeast Schizosaccharomyces pombe. S. pombe provide a well defined and readily manipulated genetic background devoid of known endogenous nuclear hormone receptors. All the receptors tested, when introduced exogenously into S. pombe, induced high levels of reporter gene activation in response to physiological concentrations of hormone ligand. In these properties, the S. pombe system exhibits significant advantages over the previously employed Saccharomyces cerevisiae system. Use of the S. pombe system permitted the elucidation of previously undescribed differences in the DNA sequence recognition properties of different isoforms of the RXR and RARs, and the identification of apparently novel forms of response element for RXRs and RARs. Intriguingly, the v-erb A allele of T3R, a transcriptional repressor in vertebrate cells, acts as a transcriptional activator both in S. cerevisiae and in the evolutionarily highly divergent S. pombe, underscoring the importance of cellular factors in the regulation of receptor transcriptional activity.
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PMID:Reconstitution of thyroid hormone receptor and retinoic acid receptor function in the fission yeast Schizosaccharomyces pombe. 787 15

The effects of retinoic acid on cell proliferation, differentiation and patterning are thought to be mediated by the various retinoic acid receptors. Different receptor types are encoded by distinct genes (alpha, beta, and gamma), whereas various isoforms within each type are encoded by splicing variants resulting from the use of alternative promoters. The only region that differs between isoforms is the N-terminal A region containing a transcriptional activating domain. It has been proposed that these alternative A regions confer distinct activities on the receptors, thus allowing each to mediate specific effects of retinoic acid, but it has been difficult to demonstrate such isoform specificity as most cells express a number of different retinoic acid receptors. In an attempt to test whether different isoforms can mediate distinct biological effects we are focusing on retinoic-acid-dependent growth inhibition of newt limb cells. We have constructed chimaeric receptors in which the retinoic acid binding domain of each of five newt retinoic acid receptors has been replaced with a thyroid hormone (T3) binding domain. These constructs were introduced individually into cells whose growth rate was then measured in the presence of T3. The chimaeric alpha 1 receptor mediated T3-dependent inhibition of proliferation that was comparable to that given by retinoic acid, whereas the alpha 2 isoform had no activity in this assay, nor did the delta 1A, delta 1B and Delta 2 receptors. When the A region was deleted from the alpha 1 chimaera it remained a potent T3-dependent transcriptional activator, but no longer mediated T3-dependent growth inhibition. In contrast, when the A region of alpha 1 was transferred to a delta chimaeric receptor, the resulting molecule was fully active in T3-dependent growth inhibition. This is the first direct evidence for isoform specificity in a biological response to retinoic acid, and demonstrates that the specificity of this response is confined to the A region.
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PMID:Receptor isoform specificity in a cellular response to retinoic acid. 876 94

Three related orphan nuclear receptors that are expressed in the brain, NGFI-B, Nurr1, and NOR-1, were studied to compare their function as transcriptional activators. NGFI-B was able to activate (in the absence of added hormone) in CV1 cells both an NGFI-B-responsive luciferase reporter gene (containing eight copies of a response element for NGFI-B upstream of a basal prolactin promoter driving the luciferase gene, NBRE(8)-LUC), a similar thyroid hormone-receptor-responsive reporter gene (TRE(3)-LUC), and a reporter gene with an authentic promoter from a Xenopus vitellogenin gene containing two binding sites for the estrogen receptor (vit-LUC). NGFI-B activated NBRE(8)-LUC and TRE(3)-LUC (but not the vitLUC) with an amino-terminal activation domain. Nurr1 was less promiscuous as a transcriptional activator, activating.the NBRE(8)-LUC better than NGFI-B, but less than NGFI-B at the other reporter genes. NOR-1 activated only the NBRE(8)-LUC reporter gene. These results indicate that closely related nuclear receptors may differentiate between response elements or promoters and that different activation mechanisms exist depending on the promoter. This may contribute to regulation of specificity of target gene expression in the brain.
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PMID:Three related brain nuclear receptors, NGFI-B, Nurr1, and NOR-1, as transcriptional activators. 886 Feb 36


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