Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q02556 (DNA-binding domain)
 6,431 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The vEts oncoprotein and its progenitor cEts1(p68) belong to a growing family of transcription factors that are related by the conserved ets domain. We show here that the ets domain and adjacent COOH-terminal amino acids are required for DNA binding by cEts1(p68). vEts differs from cEts1(p68) in both the COOH-terminal sequence and an amino acid substitution in the ets domain. The change in the COOH-terminal sequence markedly decreases its affinity for specific DNA, and the ets domain mutation further diminishes binding. vEts does not trans-activate through the ets (PEA3) motif in vivo. Surprisingly, vEts still efficiently trans-activates the promoters of two genes, stromelysin and collagenase, that are found to be overexpressed in transformed cells. The AP1 motifs of both promoters are required for efficient activation. vEts does not bind to the AP1 motif, even in the presence of cJun and cFos. The DNA-binding domain of Ets1 is required for activation through the AP1 element. Activation is inhibited by the expression of the glucocorticoid and retinoic acid receptors, suggesting that activation by Ets does not involve reversal of negative regulators of AP1. We suggest that activation is by an indirect mechanism involving activation of endogenous genes. Our results show that vEts differs from its progenitor cEts1(p68) in its trans-activating properties. The findings suggest that activation of the Jun and Fos oncoprotein pathway is important for transformation by Ets.
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PMID:Oncogenic conversion alters the transcriptional properties of ets. 132 27

The NGFI-B cDNA was previously isolated by virtue of its induction by nerve growth factor (NGF) in PC12 cells. It encodes a 61-kilodalton protein that has two regions of extensive homology with members of the steroid/thyroid hormone receptor gene family. The rat NGFI-B gene is approximately 7.6 kilobases long and is interrupted by six introns. Although the exon-intron structure of the gene is similar to those of several other members of the steroid/thyroid hormone receptor gene family, there is a novel splice site within the DNA-binding domain which suggests that NGFI-B constitutes yet another evolutionary digression from a postulated common ancestral receptor gene. Primer extension and S1 nuclease protection assays were used to determine the transcription initiation site, which displayed the heterogeneity typical of genes that lack a TATA box. Sequence analysis of the 5' flanking region revealed several GC boxes but no identifiable TATA box. Four potential AP1 binding sites were identified at nucleotides -49, -78, -222, and -242. Neither the serum response element nor the CArG box element, two sequences found in other growth factor-inducible genes, was detected in this region of the growth factor-inducible NGFI-B gene. Nevertheless, results of nuclear runoff experiments demonstrated that the NGFI-B gene was transcriptionally activated by nerve growth factor in PC12 cells. In vivo, a rapid, dramatic increase in NGFI-B mRNA was observed in the cerebral cortex, midbrain, and cerebellum of animals that experienced a convulsant-induced seizure.
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PMID:The NGFI-B gene, a transcriptionally inducible member of the steroid receptor gene superfamily: genomic structure and expression in rat brain after seizure induction. 247 23

Transcription factor AP1 is a heteromeric complex composed of the Jun and Fos proteins. It has been shown that by associating with Jun, Fos increases Jun's ability to bind DNA and activate transcription. To determine the roles of the two proteins, we undertook the functional analysis described here. We show that both the cellular Jun and its viral counterpart, v-Jun, are efficient transcriptional activators even in the absence of Fos. The Jun proteins contain at least three separate regions responsible for transcriptional activation in F9 cells, which act in an additive manner. All of these regions contain several acidic amino acid residues that appear to be functionally important and interact with a titratable target. Although trans-activation by Fos was previously shown to be dependent on the presence of Jun, by fusing Fos to a heterologous DNA-binding domain we show that once given the ability to bind DNA on its own, Fos is also an independent trans-activator. Both Jun and Fos contribute to trans-activation by the AP1 complex, and the augmentation of Jun activity by Fos is probably due to the increased DNA-binding activity of the Jun:Fos heterodimer.
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PMID:Jun and v-jun contain multiple regions that participate in transcriptional activation in an interdependent manner. 251 90

Marek's disease virus (MDV) is an avian herpesvirus that induces a variety of diseases, including T-cell lymphomas, in chickens. In latently infected, transformed lymphoid cells, very few viral transcripts or proteins are detected. We previously described a gene, meq (MDV EcoQ), which is persistently expressed in MDV-transformed tumor samples and cell lines. meq codes for a 339-amino-acid protein with a basic-leucine zipper domain near its N terminus and a proline-rich domain near its C terminus. The basic-leucine zipper domain shows homology with Jun/Fos family proteins, whereas the proline-rich domain resembles that of the WT-1 tumor suppressor protein. These structural features raise the possibility that Meq functions as a transcription factor in regulating viral latency or oncogenesis. In this report, we show that the proline-rich domain is a potent transcription activator when fused to the yeast (Saccharomyces cerevisiae) Gal4(1-147) DNA-binding domain. The transactivation activity maps to the C-terminal 130 amino acids, with the last 33 amino acids essential. In the absence of these 33 amino acids, a two-and-one-half proline-rich repeat structure was found to exhibit repression activity. We further show that Meq is able to dimerize not only with itself but also with c-Jun. Meq/c-Jun heterodimers bind to an AP1-like sequence in the meq promoter region with an affinity much greater than that of Meq/Meq or c-Jun/c-Jun homodimers. Cotransfection chloramphenicol acetyltransferase assays suggest that the Meq/c-Jun heterodimers can up-regulate Meq expression in both chicken embryo fibroblasts and F9 cells. Our data provide the first biochemical evidence that Meq is a transcriptional factor and identify c-Jun as one of Meq's interacting partners.
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PMID:Transactivation activity of Meq, a Marek's disease herpesvirus bZIP protein persistently expressed in latently infected transformed T cells. 776 61

u.v.-responsive element (URE)-binding proteins were found to include members of the AP1 and ATF transcription factor families. To elucidate the functional contribution of URE-bound proteins to the characteristics of human melanoma, we have used a dominant negative CREB cDNA which is mutated within the DNA-binding domain and cloned into a mammalian expression vector driven by the RSV promoter (KCREB). As such, KCREB is still capable of heterodimerizing with its associated proteins, yet, due to its poor binding affinity to DNA it out competes transcriptional activity mediated by those proteins. Human melanoma cells (MeWo) were transfected with KCREB and three clones, designated K1, K2, and K10 which express KCREB transcripts were then selected for further characterization. When tested for binding activities in gel shift assays, proteins prepared from the three clones exhibited a different set of complexes than the parent MeWo and control MeWo(neo) cells (transfected with empty expression vector) under normal growth conditions, and after u.v.-irradiation. Using CAT vector, driven by a tetramer URE construct, revealed a striking decrease in transcriptional activity in each of the three clones before as well as after u.v.-irradiation. When tested for radiation resistance MeWo cells were found to exhibit 42% survival to a u.v.-dose of 16 J/m2, whereas, K1, K2 and K10 exhibited only 10.2, 3.9 and 4.2% survival, respectively. Exposure to 2 Gy of X-radiation led to 62.1% survival of MeWo as compared with 18.5% of K1 and 7.7% and 6.5% of K2 and K10, respectively. While no significant differences were noticed in their growth rate, all three clones exhibited fewer, and smaller colonies in soft agar, when compared with parent cells. These findings indicate that through their transcriptional activities, CREB and its associated proteins play an important role in the acquisition of characteristic phenotypes of human melanoma cells including resistance to u.v.-irradiation.
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PMID:Expression of dominant negative CREB reduces resistance to radiation of human melanoma cells. 866 49

Recent studies support a model for signal transduction from activated receptor tyrosine kinases to Ras which, in turn, activates the pathway of the mitogen-activated protein kinase (MAPK). Although some members of the Ets transcription factor family have been shown to be activated by this signaling pathway, no data are available on the activation of the PEA3 group of Ets proteins. This group is composed of three members -- PEA3, ER81 and ERM -- which are very similar in the DNA-binding domain, the ETS domain, in the 32 residue amino-terminal acidic domain and in the 61 residue carboxy-terminal domain. First of all we demonstrated that ERM-transfected cells contain a positive labeling in the nucleus, and we concluded that a nuclear localization signal might be situated in the ETS domain. We then showed that of four putative reporter plasmids, ERM activated the artificial 3 x TORU plasmid which contains an Ets binding site contiguous to an AP1 one. This transactivation enhancement requires the presence of the ERM amino-terminal domain. In contrast, although the lack of the carboxy-terminal domain induced a decrease in transactivation, this latter domain is not crucial. By using the E74-reporter plasmid system which is not basically activated by ERM, we showed that the activation of the Ras/Raf-1/MAPK pathway significantly enhanced ERM-mediated transactivation. The deletion of the amino-terminal transactivation domain abolished the capacity of stimulated MAPK to activate ERM. We also demonstrated that ERM can also be activated through the protein kinase A (PKA), another signaling pathway. Nevertheless, the MAPK and PKA activation of ERM are not synergistic. Finally, we showed that this Ets transcription factor is in vitro phosphorylated by both activated ERK-2 and activated PKA. ERM has thus been identified as a transcription factor which is a target for two different signaling pathways and might therefore be involved in the mitogenic response of cells.
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PMID:The ETS-related transcription factor ERM is a nuclear target of signaling cascades involving MAPK and PKA. 889 21

We have previously demonstrated that transformation by Fos is critically dependent on an intact DNA-binding domain (bZip) and a functional N-terminal transactivation motif (N-TM). We now show that a novel motif (C-terminal transactivation motif [C-TM]) near the C terminus also plays an important role in both transformation and the activation of AP1-dependent transcription and that the hydrophobic amino acids in the C-TM are functionally essential. The C-TM is the most crucial element in the C-terminal transactivation domain in Fos, as indicated by its relative strength and context-independent function. The C-TM is clearly different from the previously identified HOB2 domain, located N terminally to the C-TM, and the C-terminally positioned TATA-binding protein-binding domain. We also show that the C-terminal transactivation domain strongly synergizes with the HOB1-like N-TM, even when both domains are present on different proteins within a dimeric complex, and that the C-TM plays a crucial role in this cooperation. These observations can be corroborated in a model in which multiple contacts with the basal machinery are established either to stabilize the transcription complex or to facilitate its sequential assembly.
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PMID:A novel, transformation-relevant activation domain in Fos proteins. 900 Dec 6

Thyroid hormone (T3) and retinoic acid (RA) play important roles in erythropoiesis. We found that the hematopoietic cell-specific bZip protein p45/NF-E2 interacts with T3 receptor (TR) and RA receptor (RAR) but not retinoid X receptor. The interaction is between the DNA-binding domain of the nuclear receptor and the leucine zipper region of p45/NF-E2 but is markedly enhanced by cognate ligand. Remarkably, ligand-dependent transactivation by TR and RAR is markedly potentiated by p45/NF-E2. This effect of p45/NF-E2 is prevented by maf-like protein p18, which functions positively as a heterodimer with p45/NF-E2 on DNA. Potentiation of hormone action by p45/NF-E2 requires its activation domain, which interacts strongly with the multifaceted coactivator cyclic AMP response element protein-binding protein (CBP). The region of CBP which interacts with p45/NF-E2 is the same interaction domain that mediates inhibition of hormone-stimulated transcription by AP1 transcription factors. Overexpression of the bZip interaction domain of CBP specifically abolishes the positive cross talk between TR and p45/NF-E2. Thus, positive cross talk between p45/NF-E2 and nuclear hormone receptors requires direct protein-protein interactions between these factors and with CBP, whose integration of positive signals from two transactivation domains provides a novel mechanism for potentiation of hormone action in hematopoietic cells.
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PMID:The transcriptional integrator CREB-binding protein mediates positive cross talk between nuclear hormone receptors and the hematopoietic bZip protein p45/NF-E2. 903 67

The isolation and initial characterization of the Arabidopsis thaliana SPL3 gene are described. SPL3 belongs to a gene family encoding putative transcription factors characterized by a conserved DNA-binding domain, the SBP domain. SPL3 transcription is developmentally regulated and is localized mainly in vegetative and inflorescence apical meristems, floral meristems and in leaf and floral organ primordia. SPL3 recognizes a conserved sequence motif in the promoter region of the A. thaliana floral meristem identity gene AP1. Similarly to AP1, constitutive expression of SPL3 results in early flowering. However, constitutive expression of SPL3 in an ap1 mutant background showed that AP1 is not required for the early flowering phenotype of the SPL3 transgenic plants. The function of SPL3 during flowering as well as its possible functional redundancy are discussed.
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PMID:Functional analysis of the Arabidopsis thaliana SBP-box gene SPL3: a novel gene involved in the floral transition. 930 Oct 89

The nuclear receptor SF1 is an essential mediator in ventromedial hypothalamus-pituitary-gonadal development. As with other nuclear receptors, SF1 possesses a DNA-binding domain composed of two zinc fingers and a ligand-binding domain containing a ligand-dependent activation sequence termed AF2. To dissect the domain function of SF1, we examined various SF1 mutants in mouse adrenocortical Y1 cells and human placental JEG3 cells. Destruction of the AF2 structure removed 73-90% transactivation activity, suggesting that AF2 is indispensable for transactivation. Mutants carrying the DNA-binding domain but lacking the AF2 or the ligand-binding domain blocked the activity of normal SF1. Disrupting the zinc finger diminished the dominant negative effect of mutant. Cotransfection of SF1 with AP1 showed that the two transcription factors cooperated to activate gene expression. Some mutants lost the synergistic action with AP1, while some retained partial activity. These experiments delineate the functional domains of SF1.
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PMID:Function of steroidogenic factor 1 (SF1) ligand-binding domain in gene activation and interaction with AP1. 975 27


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