UNIPROT:P51532 - FACTA Search

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

Synthetic steroid hormone antagonists are clinically important compounds that regulate physiological responses to steroid hormones. The antagonists bind to the hormone receptors, which are ligand-inducible transcription factors, and modulate their gene-regulatory activities. In most instances, a steroid receptor, such as progesterone receptor (PR) or estrogen receptor (ER), is transcriptionally inactive when complexed with an antagonist and competitively inhibits transactivation of a target steroid-responsive gene by the cognate hormone-occupied receptor. In certain cellular and promoter contexts, however, antagonist-occupied PR or ER acquires paradoxical agonist-like activity. The cellular mechanisms that determine the switch from the negative to the positive mode of transcriptional regulation by an antagonist-bound steroid receptor are unknown. We now provide strong evidence supporting the existence of a cellular inhibitory cofactor that interacts with the B form of human PR (PR-B) complexed with the antiprogestin RU486 to maintain it in a transcriptionally inactive state. In the presence of unliganded thyroid hormone receptor (TR) or ER complexed with the antiestrogen 4-hydroxytamoxifen, which presumably sequesters a limiting pool of the inhibitory cofactor, RU486-PR-B functions as a transcriptional activator of a progesterone-responsive gene even in the absence of hormone agonist. In contrast, hormone-occupied TR or ER fails to induce transactivation by RU486-PR-B. Recent studies revealed that a transcriptional corepressor, NCoR (nuclear receptor corepressor), interacts with unliganded TR but not with liganded TR. Interestingly, coexpression of NCoR efficiently suppresses the partial agonistic activity of antagonist-occupied PR-B but fails to affect transactivation by agonist-bound PR-B. We further demonstrate that RU486-PR-B interacts physically with NCoR in vitro. These novel observations suggest that the inhibitory cofactor that associates with RU486-PR-B and represses its transcriptional activity is either identical or structurally related to the corepressor NCoR. We propose that cellular mechanisms that determine the switch from the antagonistic to the agonistic activity of RU486-PR-B involve removal of the corepressor from the antagonist-bound receptor so that it can effect partial but significant gene activation.
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PMID:A nuclear receptor corepressor modulates transcriptional activity of antagonist-occupied steroid hormone receptor. 954 87

The Pax-5 gene codes for the transcription factor BSAP which is essential for the progression of adult B lymphopoiesis beyond an early progenitor (pre-BI) cell stage. Although several genes have been proposed to be regulated by BSAP, CD19 is to date the only target gene which has been genetically confirmed to depend on this transcription factor for its expression. We have now taken advantage of cultured pre-BI cells of wild-type and Pax-5 mutant bone marrow to screen a large panel of B lymphoid genes for additional BSAP target genes. Four differentially expressed genes were shown to be under the direct control of BSAP, as their expression was rapidly regulated in Pax-5-deficient pre-BI cells by a hormone-inducible BSAP-estrogen receptor fusion protein. The genes coding for the B-cell receptor component Ig-alpha (mb-1) and the transcription factors N-myc and LEF-1 are positively regulated by BSAP, while the gene coding for the cell surface protein PD-1 is efficiently repressed. Distinct regulatory mechanisms of BSAP were revealed by reconstituting Pax-5-deficient pre-BI cells with full-length BSAP or a truncated form containing only the paired domain. IL-7 signalling was able to efficiently induce the N-myc gene only in the presence of full-length BSAP, while complete restoration of CD19 synthesis was critically dependent on the BSAP protein concentration. In contrast, the expression of the mb-1 and LEF-1 genes was already reconstituted by the paired domain polypeptide lacking any transactivation function, suggesting that the DNA-binding domain of BSAP is sufficient to recruit other transcription factors to the regulatory regions of these two genes. In conclusion, these loss- and gain-of-function experiments demonstrate that BSAP regulates four newly identified target genes as a transcriptional activator, repressor or docking protein depending on the specific regulatory sequence context.
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PMID:Identification of BSAP (Pax-5) target genes in early B-cell development by loss- and gain-of-function experiments. 954 44

The progesterone receptor (PR) occurs in two major forms, the full-length PRB and the amino-truncated PRA, which lacks 164 amino-terminal residues. PRB functions as a strong transcriptional activator of progesterone-responsive genes, whereas PRA is inactive in several cell types where it may even act as a trans-dominant repressor of PRB and other steroid receptors, like the glucocorticoid receptor or, reportedly, the estrogen receptor. We initially observed that a PR deleted of its entire amino domain (PR538-C) is incapable of trans-repressing PRB or glucocorticoid receptor, suggesting that a negative modulation domain must be contained in the region between position 165 and 538. After testing progressive deletion mutants and chimeras, we demonstrate that this negative modulating domain is confined within 120 residues in the amino-terminal region and that it contains a subdomain of 40 residues that is crucial for intermolecular transrepression. Duplication, deletion, and transplantation of the negative modulation domain show that the negative modulation domain has only a limited functional autonomy. In our hands, transrepression of estrogen receptor could not be substantiated, and, under our conditions, at least an equimolar concentration of PRA expression plasmid is required for transrepression. Our deletion studies reveal domains that correlate with strong homology patches between the amino-terminal domains of mammalian and avian PR.
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PMID:Definition of a negative modulation domain in the human progesterone receptor. 973 2

GAL4.estrogen receptor.VP16 (GAL4.ER.VP16), which contains the GAL4 DNA-binding domain, the human ER hormone binding (AF-2) domain, and the VP16 activation domain, functions as a hormone-dependent transcriptional activator in yeast (Louvion, J.-F., Havaux-Copf, B., and Picard, D. (1993) Gene (Amst.) 131, 129-134). Previously, we showed that this activator can remodel chromatin in yeast in a hormone-dependent manner. In this work, we show that a weakened VP16 activation domain in GAL4.ER.VP16 still allows hormone-dependent chromatin remodeling, but mutations in the AF-2 domain that abolish activity in the native ER also eliminate the ability of GAL4.ER.VP16 to activate transcription and to remodel chromatin. These findings suggest that an important role of the AF-2 domain in the native ER is to mask the activation potential of the AF-1 activation domain in the unliganded state; upon ligand activation, a conformational change releases AF-2-mediated repression and transcriptional activation ensues. We also show that the AF-2 domain, although inactive at simple promoters on its own in yeast, can enhance transcription by the MCM1 activator in hormone-dependent manner, consistent with its having a role in activation as well as repression in the native ER.
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PMID:Mutations in the AF-2/hormone-binding domain of the chimeric activator GAL4.estrogen receptor.VP16 inhibit hormone-dependent transcriptional activation and chromatin remodeling in yeast. 985 87

Estrogen receptor related alpha (ERRalpha) is an orphan nuclear receptor that is closely related to the estrogen receptor. It is expressed in a variety of adult and embryonic tissues (in particular, at the onset of ossification), as well as in several osteoblastic cell lines. ERRalpha acts as a site-specific, cell-specific transcriptional activator. Here, we show that ERRalpha transactivates the promoter of the mouse osteopontin (OPN) gene, the product of which is a marker of the late stages of osteoblastic differentiation. This effect is cell specific and is exerted through derivatives of the ERRalpha response element. Overexpression of ERRalpha in three different osteoblast-like cell lines results in an elevation of the amount of OPN-corresponding mRNA. Therefore, OPN is a target gene for ERRalpha, pointing to the role of the latter in osteoblast differentiation.
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PMID:Activation of the osteopontin promoter by the orphan nuclear receptor estrogen receptor related alpha. 986 1

The interaction between beta-catenin and LEF-1/TCF transcription factors plays a pivotal role in the Wnt-1 signaling pathway. The level of beta-catenin is regulated by partner proteins, including glycogen synthase kinase-3beta (GSK-3beta) and the adenomatous polyposis coli (APC) tumor suppressor protein. Genetic defects in APC are responsible for a heritable predisposition to colon cancer. APC protein and GSK-3beta bind beta-catenin, retain it in the cytoplasm, and facilitate the proteolytic degradation of beta-catenin. Abrogation of this negative regulation allows beta-catenin to translocate to the nucleus and to form a transcriptional activator complex with the DNA-binding protein lymphoid-enhancing factor 1 (LEF-1). This complex is thought to be involved in tumorigenesis. Here we show that covalent linkage of LEF-1 to beta-catenin and to transcriptional activation domains derived from the estrogen receptor or the herpes simplex virus protein VP16 generates transcriptional regulators that induce oncogenic transformation of chicken embryo fibroblasts. The chimeras between LEF-1 and beta-catenin or VP16 are constitutively active, whereas fusions of LEF-1 to the estrogen receptor are regulatable by estrogen. These experiments document the oncogenicity of transactivating LEF-1 and show that the transactivation domain normally provided by beta-catenin can be replaced by heterologous activation domains. These results suggest that the transactivating function of the LEF-1/beta-catenin complex is critical for tumorigenesis and that this complex transforms cells by activating specific LEF-1 target genes.
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PMID:Nuclear endpoint of Wnt signaling: neoplastic transformation induced by transactivating lymphoid-enhancing factor 1. 987 85

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

Genistein, a natural flavone found in soy has been postulated to be responsible for lowering the rate of breast cancer in Asian women. Our previous studies have shown that genistein exerts multiple suppressive effects on both estrogen receptor positive (ER+) as well as estrogen receptor negative (ER-) human breast carcinoma lines suggesting that the mechanisms of these effects may be independent of ER pathways. In the present study however we provide evidence that in the ER+ MCF-7, T47D and 549 lines but not in the ER-MDA-MB-231 and MDA-MB-468 lines both presumed "ER-dependent" and "ER-independent" actions of genistein are mediated through ER pathways. Genistein's antiproliferative effects are estrogen dependent in these ER+ lines, being more pronounced in estrogen-containing media and in the presence of exogenous 17-beta estradiol. Genistein also inhibits the expression of ER-downstream genes including pS2 and TGF-beta in these ER+ lines and this inhibition is also dependent on the presence of estrogen. Genistein inhibits estrogen-induced protein tyrosine kinase (PTK) activity. Genistein is only a weak transcriptional activator and actually decreases ERE-CAT levels induced by 17-beta estradiol in the ER+ lines. Genistein also decreases steady state ER mRNA only in the presence of estrogen in the ER+ lines thereby manifesting another suppression of and through the ER pathway. Our observations resurrect the hypothesis that genistein functions as a "good estrogen" in ER+ breast carcinomas. Since chemopreventive effects of genistein would be targeted to normal ER-positive ductal-lobular cells of the breast, this "good estrogen" action of genistein is most relevant to our understanding of chemoprevention.
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PMID:Genistein's "ER-dependent and independent" actions are mediated through ER pathways in ER-positive breast carcinoma cell lines. 1095 3

The vitamin D receptor (VDR) normally functions as a ligand-dependent transcriptional activator. Here we show that, in the presence of Ets-1, VDR stimulates the prolactin promoter in a ligand-independent manner, behaving as a constitutive activator. Mutations in the AF2 domain abolish vitamin D-dependent transactivation but do not affect constitutive activation by Ets-1. Therefore, in contrast with the actions of vitamin D, activation by Ets-1 is independent of the AF2 domain. Ets-1 also conferred a ligand-independent activation to the estrogen receptor and to peroxisome proliferator-activated receptor alpha. In addition, Ets-1 cooperated with the unliganded receptors to stimulate the activity of reporter constructs containing consensus response elements fused to the thymidine kinase promoter. There is a direct interaction of the receptors with Ets-1 which requires the DNA binding domains of both proteins. Interaction with Ets-1 induces a conformational change in VDR which can be detected by an increased resistance to proteolytic digestion. Furthermore, a retinoid X receptor-VDR heterodimer in which both receptors lack the core C-terminal AF2 domain can recruit coactivators in the presence, but not in the absence, of Ets-1. This suggests that Ets-1 induces a conformational change in the receptor which creates an active interaction surface with coactivators even in the AF2-defective mutants. These results demonstrate the existence of a novel mechanism, alternative to ligand binding, which can convert an unliganded receptor from an inactive state into a competent transcriptional activator.
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PMID:Association with Ets-1 causes ligand- and AF2-independent activation of nuclear receptors. 1107 80

Treatment of newborn female rats with estrogens significantly inhibits the growth and differentiation of the ovary. To understand the molecular mechanism of estrogen action in the induction of abnormal ovary, we examined the expression profiles of steroidogenic factor 1 (SF-1) and several of its target genes in the developing ovaries after neonatal exposure to synthetic estrogen, estradiol benzoate (EB) by using reverse transcriptase polymerase chain reaction, in situ hybridization, and immunohistochemistry. Morphologic examination indicated inhibitory effects of estrogen on the stratification of follicles and development of theca and interstitial gland during postnatal ovarian differentiation. The expression of the steroidogenic acute regulatory protein (StAR) and cholesterol side-chain cleavage cytochrome P450 (P450(SCC)), which are both essential for steroid biosynthesis, markedly decreased in theca and interstitial cells throughout the postnatal development of the EB-treated ovary. However, expression of the transcriptional activator of the two genes, SF-1 was unaffected in theca and interstitial cells, although the number of these cells was lower in the EB-treated ovary than in the control ovary. The expression of the estrogen mediator, estrogen receptor-alpha (ER-alpha), diminished specifically in theca cells at P6 and recovered by P14 in the EB-treated ovary. These results indicate that the effect of estrogens is mediated by means of ER-alpha resulting in the down-regulation of StAR and P450(SCC) genes during early postnatal development of the ovary. These results suggest that the abnormal ovarian development by neonatal estrogen treatment is closely correlated with the reduced steroidogenic activity, and the data obtained by using this animal model may account in part the mechanism for aberrant development and function of the ovary in prenatally estrogen-exposed humans.
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PMID:Neonatal estrogen exposure inhibits steroidogenesis in the developing rat ovary. 1150 Sep 81

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