Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutation of the orphan nuclear receptor RORalpha results in a severe impairment of cerebellar development by unknown mechanisms. We have found that RORalpha activates transcription from only a subset of sites to which it binds strongly as a monomer. RORalpha also selectively binds as a homodimer to a direct repeat of this monomer site with a 2-bp spacing between the AGGTCA sequences (Rev-DR2 site) and is a much more potent transcriptional activator on this site than on monomer sites or other direct repeats. To better understand the transcriptional regulatory functions of RORalpha, we fused its C terminus to a heterologous DNA-binding domain. Mutational analysis revealed that RORalpha contains both transcriptional activation and transcriptional repression domains, with the repression domain being more active in some cell types. The abilities of RORalpha polypeptides to repress transcription correlate with their abilities to interact with the nuclear receptor corepressors N-CoR and SMRT in vitro. However, the AF2 region of RORalpha inhibits corepressor interaction on DNA, consistent with the lack of repression by the full-length receptor. Thus, transcriptional regulation by RORalpha is complex and likely to be regulated in a cell type- and target gene-specific manner.
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PMID:Transcriptional activation and repression by RORalpha, an orphan nuclear receptor required for cerebellar development. 932 55

The ecdysone receptor (EcR) is a member of the large family of nuclear hormone receptors, which are ligand regulated transcription factors. In general, ligand converts these receptors into a transcriptional activator. Some vertebrate nuclear hormone receptors, such as the thyroid hormone and retinoic acid receptors, silence gene expression in the absence of ligand. EcR is involved in fly metamorphosis and is used in vertebrates as an inducible system for expression of transgenes. Here, we show that a Drosophila receptor, the EcR, harbours an autonomous silencing function in its carboxy-terminus. Interestingly, EcR mediates also silencing in vertebrate cells. In concordance with this EcR interacts with the corepressors SMRT and N-CoR, while addition of ligand reduces this interaction. Conversely, the v-erbA oncogene product, a thyroid hormone receptor derivative, mediates silencing in Drosophila cells. Thus, our data suggest the involvement of an evolutionarily conserved mechanism by which nuclear hormone receptors mediate gene silencing in multicellular organisms.
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PMID:EcR interacts with corepressors and harbours an autonomous silencing domain functional in both Drosophila and vertebrate cells. 1036 14

In humans, the biological response to progesterone is mediated by two forms of the progesterone receptor (hPR-A; 94kDa and hPR-B; 114kDa). These two isoforms are transcribed from distinct, estrogen-inducible promoters within a single-copy progesterone receptor (PR) gene; the only difference between them is that the first 164 amino acids of hPR-B are absent in hPR-A. In most cell lines, hPR-A functions as a transcriptional repressor of progesterone-responsive promoters, whereas hPR-B functions as a transcriptional activator of the same genes. The observation, made in the early 1990s, that shorter isoforms of some transcriptional activators can act as transrepressors of the transcriptional activity of the larger isoforms, initiated a line of investigation that led to the discovery that hPR-A is a strong transrepressor of hPR-B activity. Interestingly, hPR-A also functions as a transdominant repressor of the transcriptional activity of the estrogen, glucocorticoid, androgen, and mineralocorticoid receptors. A specific inhibitory domain (ID) within hPR-A responsible for this activity has been mapped to the extreme amino terminus of the receptor. Interestingly, although this inhibitory domain is contained within both PR isoforms, its activity is manifest only in the context of hPR-A. The identification of a discrete inhibitory region within hPR-A, whose activity was masked in the context of hPR-B, suggests that these two receptor isoforms may interact with different proteins (transcription factors, co-activators, co-repressors) within the cell. In support of this hypothesis, we have recently observed that the co-repressor SMRT (silencing mediator of retinoid and thyroid receptors) interacts much more tightly with hPR-A than with hPR-B. This important finding led to the initial conclusion that the ability of hPR-A to repress hPR-B transcriptional activity could occur as a consequence of hPR-B/A heterodimerization, where the presence of SMRT in the complex could prevent transcriptional activation. The observation, however, that hPR-A also inhibits human estrogen receptor (hER) transcriptional activity, a receptor with which hPR-A is not able to heterodimerize, suggests that there must be additional complexity. This chapter outlines what is known about the mechanism of action of hPR-A and hPR-B and how this knowledge has enhanced our understanding of PR pharmacology.
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PMID:The A and B isoforms of the human progesterone receptor: two functionally different transcription factors encoded by a single gene. 1054 81

EBNA2 is essential for Epstein-Barr virus (EBV) immortalization of B lymphocytes. EBNA2 functions as a transcriptional activator and targets responsive promoters through interaction with the cellular DNA binding protein CBF1. We have examined the mechanism whereby EBNA2 overcomes CBF1-mediated transcriptional repression. A yeast two-hybrid screen performed using CBF1 as the bait identified a protein, SKIP, which had not previously been recognized as a CBF1-associated protein. Protein-protein interaction assays demonstrated contacts between SKIP and the SMRT, CIR, Sin3A, and HDAC2 proteins of the CBF1 corepressor complex. Interestingly, EBNA2 also interacted with SKIP in glutathione S-transferase affinity and mammalian two-hybrid assays and colocalized with SKIP in immunofluorescence assays. Interaction with SKIP was not affected by mutation of EBNA2 conserved region 6, the CBF1 interaction region, but was abolished by mutation of conserved region 5. Mutation of conserved region 5 also severely impaired EBNA2 activation of a reporter containing CBF1 binding sites. Thus, interaction with both CBF1 and SKIP is necessary for efficient promoter activation by EBNA2. A model is presented in which EBNA2 competes with the SMRT-corepressor complex for contacts on SKIP and CBF1.
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PMID:A role for SKIP in EBNA2 activation of CBF1-repressed promoters. 1064 67

The human progesterone receptor (PR) exists as two functionally distinct isoforms, hPRA and hPRB. hPRB functions as a transcriptional activator in most cell and promoter contexts, while hPRA is transcriptionally inactive and functions as a strong ligand-dependent transdominant repressor of steroid hormone receptor transcriptional activity. Although the precise mechanism of hPRA-mediated transrepression is not fully understood, an inhibitory domain (ID) within human PR, which is necessary for transrepression by hPRA, has been identified. Interestingly, although ID is present within both hPR isoforms, it is functionally active only in the context of hPRA, suggesting that the two receptors adopt distinct conformations within the cell which allow hPRA to interact with a set of cofactors that are different from those recognized by hPRB. In support of this hypothesis, we identified, using phage display technology, hPRA-selective peptides which differentially modulate hPRA and hPRB transcriptional activity. Furthermore, using a combination of in vitro and in vivo methodologies, we demonstrate that the two receptors exhibit different cofactor interactions. Specifically, it was determined that hPRA has a higher affinity for the corepressor SMRT than hPRB and that this interaction is facilitated by ID. Interestingly, inhibition of SMRT activity, by either a dominant negative mutant (C'SMRT) or histone deacetylase inhibitors, reverses hPRA-mediated transrepression but does not convert hPRA to a transcriptional activator. Together, these data indicate that the ability of hPRA to transrepress steroid hormone receptor transcriptional activity and its inability to activate progesterone-responsive promoters occur by distinct mechanisms. To this effect, we observed that hPRA, unlike hPRB, was unable to efficiently recruit the transcriptional coactivators GRIP1 and SRC-1 upon agonist binding. Thus, although both receptors contain sequences within their ligand-binding domains known to be required for coactivator binding, the ability of PR to interact with cofactors in a productive manner is regulated by sequences contained within the amino terminus of the receptors. We propose, therefore, that hPRA is transcriptionally inactive due to its inability to efficiently recruit coactivators. Furthermore, our experiments indicate that hPRA interacts efficiently with the corepressor SMRT and that this activity permits it to function as a transdominant repressor.
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PMID:The opposing transcriptional activities of the two isoforms of the human progesterone receptor are due to differential cofactor binding. 1075 95

Octamer transcription factor-1 (Oct-1) is a member of the POU (Pit-1, Oct-1, unc-86) family of transcription factors and is involved in the transcriptional regulation of a variety of gene expressions related to cell cycle regulation, development, and hormonal signals. It has been shown that Oct-1 acts not only as a transcriptional activator but also as a transcriptional repressor for certain genes. The mechanism of the repressive function of Oct-1 has not been well understood. Here we demonstrate by using the glutathione S-transferase pull-down assays and coimmunoprecipitation assays that the POU domain of Oct-1 directly interacts with a silencing mediator for retinoid and thyroid hormone receptors (SMRT). The interaction surfaces are located in the C-terminal region of SMRT, which are different from previously described silencing domains I and II or receptor interacting domains I and II. In transient transfection assays in COS1 cells, overexpression of SMRT attenuated the augmentation of Oct-1 transcriptional activity by OBF-1/OCA-B, activator for Oct-1. In pull-down assays, increasing amounts of SMRT could compete the binding of OCA-B to Oct-1 POU domain. The activity of Oct-1 could be determined by a regulated balance between SMRT and OCA-B. Furthermore, cotransfected unliganded thyroid hormone receptor enhanced the transactivation by Oct-1, and addition of 3,3',5-tri-iodo-l-thyronine obliterated the stimulatory effects. Consequently, in the presence of cotransfected thyroid hormone receptor, the octamer response element acts as an element negatively regulated by 3,3',5-tri-iodo-l-thyronine. The results suggest that the transcriptional activity of Oct-1 can be modulated by interaction through its POU domain by a silencing mediator SMRT resulting in the cross-talk between Oct-1 and nuclear receptors.
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PMID:Silencing mediator for retinoid and thyroid hormone receptors interacts with octamer transcription factor-1 and acts as a transcriptional repressor. 1113 19