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)

Three of the ets oncogene superfamily members v-ets, Spi-1/PU.1 and Fli-1, have been shown to be directly involved in retroviral-mediated acute erythroleukemias. The Fli-1 gene was found to be rearranged in 75% of the erythroleukemias induced by Friend murine leukemia virus (F-MuLV), suggesting that it could play a key role in cellular transformation. We have previously isolated and characterized the human Fli-1 gene and have found it to be highly homologous (80%) to the human erg-2 gene. Human Fli-1 was also shown to be rearranged in Ewing's sarcoma cases, in which the amino-terminal region of the Fli-1 gene was replaced with a novel coding region of a putative RNA-binding protein, EWS. In this report, we show that the recombinant Fli-1 protein expressed in bacteria binds to DNA in a sequence-specific manner. It appears that Fli-1 and erg proteins fall into the category of ets proteins that recognize limited ets target sequences, unlike c-ets-1, ets-2 and Elk-1. The Fli-1 gene was found to activate the transcription of the reporter gene that was linked to Fli-1 target sequences, suggesting that Fli-1 is a sequence-specific transcriptional activator. Deletion analysis revealed the presence of two autonomous transcriptional activation domains, one at the amino-terminal region (amino-terminal transcriptional activation domain, ATA) and the other at the carboxy-terminal region (carboxy-terminal transcriptional activation domain, CTA). Secondary structural analysis of ATA and CTA domains revealed the presence of helix-loop-helix (H-L-H) and/or turn-loop-turn (T-L-T) regions. From these results it appears that a portion of the Fli-1 ATA domain (H-L-H region) was replaced by the amino-terminal domain of EWS gene in Ewing's sarcoma cases. Therefore alteration in the transcriptional activation function of Fli-1 may be responsible for human malignancies such as sarcomas, leukemias and lymphomas in which this gene is rearranged.
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PMID:Analysis of the DNA-binding and transcriptional activation functions of human Fli-1 protein. 833 42

Nuclear levels of c-Jun, JunB, c-Fos, and LRF-1 (liver regeneration factor) are high for a large fraction of the G1 phase in regenerating liver and mitogen-stimulated hepatic cells. Previously, JunB was regarded as a less potent transcriptional activator than c-Jun that could also function as a repressor. However, we found that, like c-Jun, JunB alone or LRF-1/JunB strongly transactivates a cAMP-responsive promoter. Unlike c-Jun, JunB represses several AP-1 or activator of transcription factor site-containing promoters, and this inhibition is greatly enhanced in the presence of LRF-1. Here, we identify separate regions of JunB required for trans-activation and repression of these promoters. Deletion analysis shows that the region involved in trans-activation function is highly conserved among all Jun family members and corresponds to activator domain (A1) of c-Jun. In contrast, repression is maximal in the presence of both the DNA-binding domain and a region proximal to the basic region that is highly divergent among Jun proteins. Functional distinctions between Jun proteins during induction of the growth response and tumorigenesis may be accounted for by promoter-specific activation and repression mediated by regional differences in Jun family proteins.
Cancer Res 1993 Aug 15
PMID:Promoter-specific trans-activation and inhibition mediated by JunB. 833 92

The ets oncogene superfamily codes for a family of transcriptional factors that are involved in gene regulation not only by autonomous DNA binding but also by indirect DNA binding through interaction with cellular factors. We have previously shown that a member of this superfamily, elk-1, is a sequence specific transcriptional activator, which forms a serum response factor (SRF) dependent ternary complex with serum response element (SRE) similar to p62TCF. We describe here an alternatively spliced variant of elk-1 named delta elk-1, which has lost the SRF interaction domain, negative regulatory DNA binding domain, and part of the elk-1 DNA binding domain. This variant elk-1 protein has lost the capacity to form a SRF dependent ternary complex with SRE and to activate fos transcription. Since this splice variant lacks part of the ets DNA binding domain, it binds to DNA with a specificity that is different from that of the full length elk-1 protein. Therefore differential splicing within the DNA binding and protein-protein interaction domains of transcriptional factors can generate proteins with modulated DNA binding specificities and transcriptional regulation. Thus it is conceivable that variant elk-1 might function by competing for some of the elk-1 target sequences (like SRE) and thereby block the transcriptional activation of fos by SRF and elk-1. Alternately, variant elk-1 protein may be the repressor, recruited by the SRE bound SRF for c-fos repression, or it may have an altogether different function. Therefore, elk-1 appears to fall in the category of genes that encode activators and repressors through the mechanism of differential splicing.
Cancer Res 1993 Jan 15
PMID:Delta elk-1, a variant of elk-1, fails to interact with the serum response factor and binds to DNA with modulated specificity. 841 10

The recently cloned ATM gene has been shown to bear considerable homology to phosphatidylinositol 3 kinases and, therefore, its product may function in signal transduction. In this study, we report constitutively elevated levels of two IFN-beta-inducible proteins, ubiquitin cross-reactive protein (UCRP), and low molecular weight protein (LMP2), in human fibroblasts with the inherited disease ataxia telangiectasia (AT). Using immunoblotting, it was found that a M(r) 15,000 band representing free UCRP was hardly detectable in normal cells, while it was the predominant band in AT cells. Similarly, the expression of a M(r) 23,000 protein, LMP2 was found to be higher in AT cells than in normal cells. Culturing three successive passages of the AT cell line in the presence of different concentrations of neutralizing antibodies against IFN-beta caused partial and complete reduction, respectively, of the free UCRP and LMP2 signals to normal levels. These results indicate that UCRP and LMP2 pools may be basally elevated in AT cells due to constitutive activation of the IFN-beta induction pathway and are in keeping with the recently reported constitutive activation of the NF-kappaB transcriptional activator in AT cells.
Cancer Res 1996 Feb 01
PMID:Elevation of interferon beta-inducible proteins in ataxia telangiectasia cells. 856 49

The transcriptional activator IFN regulatory factor 1 (IRF-1) and its antagonistic repressor IRF-2 are regulators of the IFN system. IRF-1 also manifests tumor suppressive activity, and its inactivation could contribute to the development of human hematopoietic malignancies. Here, we report the identification of the lysyl oxidase gene as a target gene of IRF-1. An IRF response element was identified in the lysyl oxidase gene promoter. We also demonstrate that the transformed phenotype of ras-expressing embryonic fibroblasts with a null mutation in the IRF-1 allele could be suppressed by the expression of the lysyl oxidase cDNA, implicating its potential role in tumor suppression. Thus, the regulation of the lysyl oxidase gene by IRF-1 could contribute to the multistep process of malignant transformation.
Cancer Res 1996 May 15
PMID:Identification of the lysyl oxidase gene as target of the antioncogenic transcription factor, IRF-1, and its possible role in tumor suppression. 862 21

Pseudohyphal differentiation in Saccharomyces cerevisiae was first described as a response of diploid cells to nitrogen limitation. Here we report that haploid and diploid starch-degrading S. cerevisiae strains were able to switch from a yeast form to a filamentous pseudohyphal form in response to carbon limitation in the presence of an ample supply of nitrogen. Two genes, MSS10 and MUC1, were cloned and shown to be involved in pseudohyphal differentiation and invasive growth. The deletion of MSS10 resulted in extremely reduced amounts of pseudohyphal differentiation and invasive growth, whereas the deletion of MUC1 abolished pseudohyphal differentiation and invasive growth completely. Mss10 appears to be a transcriptional activator that responds to nutrient limitation and coregulates the expression of MUC1 and the STA1-3 glucoamylase genes, which are involved in starch degradation. MUC1 encodes a 1367-amino acid protein, containing several serine/threonine-rich repeats. Muc1 is a putative integral membrane-bound protein, similar to mammalian mucin-like membrane proteins that have been implicated to play a role in the ability of cancer cells to invade other tissues.
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PMID:Muc1, a mucin-like protein that is regulated by Mss10, is critical for pseudohyphal differentiation in yeast. 871 Aug 86

Transcription factors/activators are a group of proteins that bind to specific consensus sequences (cis elements) in the promoter regions of downstream target/effector genes and transactivate or repress effector gene expression. The up- or downregulation of effector genes will ultimately lead to many biological changes such as proliferation, growth suppression, differentiation, or senescence. Transcription factors are subject to transcriptional and posttranslational regulation. This review will focus on the redox (reduction/oxidation) regulation of transcription factors/activators with emphasis on p53, AP-1, and NF-kappa B. The redox regulation of transcriptional activators occurs through highly conserved cysteine residues in the DNA binding domains of these proteins. In vitro studies have shown that reducing environments increase, while oxidizing conditions inhibit sequence-specific DNA binding of these transcriptional activators. When intact cells have been used for study, a more complex regulation has been observed. Reduction/oxidation can either up- or downregulate DNA binding and/or transactivation activities in transcriptional activator-dependent as well as cell type-dependent manners. In general, reductants decrease p53 and NF-kappa B activities but dramatically activate AP-1 activity. Oxidants, on the other hand, greatly activate NF-kappa B activity. Furthermore, redox-induced biochemical alterations sometimes lead to change in the biological functions of these proteins. Therefore, differential regulation of these transcriptional activators, which in turn, regulate many target/effector genes, may provide an additional mechanism by which small antioxidant molecules play protective roles in anticancer and antiaging processes. Better understanding of the mechanism of redox regulation, particularly in vivo, will have an important impact on drug discovery for chemoprevention and therapy of human disease such as cancer.
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PMID:Redox regulation of transcriptional activators. 885 44

A novel cDNA, TR2L, isolated from murine NIH 3T3 fibroblasts, was found to modulate tumor necrosis factor (TNF)-mediated apoptosis in murine L929 fibrosarcoma cells. The full-length cDNA (853 bp) encodes a predicted coding region of 56 amino acids (6.3 kD), with 53.6% identity to the C-terminus of rat transcriptional activator FE65. When expressed stably in L929 cells, TR2L protein inhibited TNF cytotoxic response. In contrast, TR2L enhanced anti-Fas antibodies/actinomycin D (ActD)-mediated L929 apoptosis. Alteration of TR2L function occurred by tagging this protein with a 6xHis fragment to the N-terminus (designated 6xH-TR2L). L929 cells which stably expressed 6xH-TR2L acquired a significantly enhanced TNF apoptotic response and increased genomic DNA fragmentation compared to control cells. Enhanced cell death also occurred in these 6xH-TR2L-expressing cells under serum starvation conditions. In contrast, the anti-Fas/ActD-mediated apoptosis was blocked by the 6xH-TR2L protein. Functional role of TR2L protein in regulation of cancer cell susceptibility to TNF-and Fas ligand-mediated apoptosis is suggested.
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PMID:Regulation of tumor necrosis factor-and Fas-mediated apoptotic cell death by a novel cDNA TR2L. 885 35

Uncontrolled cellular proliferation is the hallmark of human malignant brain tumors. Their growth proceeds inexorably, in part because their cellular constituents have an altered genetic code that enables them to evade the checks and balances of the normal cell cycle. Recently, a number of major advances in molecular biology have led to the identification of several critical genetic and enzymatic pathways that are disturbed in cancer cells resulting in uncontrolled cell cycling. We now know that the progression of a cell through the cell cycle is controlled in part by a series of protein kinases, the activity of which is regulated by a group of proteins called cyclins. Cyclins act in concert with the cyclin-dependent kinases (CDKs) to phosphorylate key substrates that facilitate the passage of the cell through each phase of the cell cycle. A critical target of cyclin-CDK enzymes is the retinoblastoma tumor suppressor protein, and phosphorylation of this protein inhibits its ability to restrain activity of a family of transcription factors (E2F family), which induce expression of genes important for cell proliferation. In addition to the cyclins and CDKS, there is an emerging family of CDK inhibitors, which modulate the activity of cyclins and CDKs. CDK inhibitors inhibit cyclin-CDK complexes and transduce internal or external growth-suppressive signals, which act on the cell cycle machinery. Accordingly, all CDK inhibitors are candidate tumor suppressor genes. It is becoming clear that a common feature of cancer cells is the abrogation of cell cycle checkpoints, either by aberrant expression of positive regulators (for example, cyclins and CDKs) or the loss of negative regulators, including p21Cip1 through loss of function of its transcriptional activator p53, or deletion or mutation of p16ink4A (multiple tumor suppressor 1/CDKN2) and the retinoblastoma tumor suppressor protein. In this review, we describe in detail our current knowledge of the normal cell cycle and how it is disturbed in cancer cells. Because there have now been a number of recent studies showing alterations in cell cycle gene expression in human brain tumors, we will review the derangements in both the positive and negative cell cycle regulators that have been reported for these neoplasms. A thorough understanding of the molecular events of the cell cycle may lead to new opportunities by which astrocytoma cell proliferation can be controlled either pharmacologically or by gene transfer techniques.
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PMID:Current concepts in neuro-oncology: the cell cycle--a review. 914 59

Two ets family members, namely erg and Fli-1 are fused with two EWS family members namely EWS and TLS/FUS as a result of chromosome translocation in human solid tumors and leukemias. EWS-erg and EWS-Fli-1, which are involved in greater than 95% of Ewing family of tumors, were shown to function as transcriptional activators. TLS/FUS-erg, which is involved in human myeloid leukemias also functions as a transcriptional activator. Expression of these fusion proteins (EWS-erg and EWS-Fli-1) are shown to be essential for maintaining the oncogenic and tumorigenic properties of tumor cells. Cancer is thought to be caused not only by uncontrolled cell proliferation but also by deregulation of programmed cell death. Therefore, we have studied the role of normal (Fli-1 and erg) and aberrant fusion proteins (EWS-erg, EWS-Fli-1 and TLS/FUS-erg) in apoptosis. We have found that expression of normal (Fli-1 and erg) and aberrant fusion proteins inhibit the apoptosis of NIH3T3 cells induced by either serum deprivation or by treatment with calcium ionophore. We have also observed similar suppression of apoptosis in Ewing's sarcoma cells expressing EWS-Fli-1 and EWS-erg proteins suggesting that these fusion proteins may be responsible for the decreased ability of these tumor cells to undergo apoptosis. Inhibition of the expression of these aberrant fusion proteins by antisense RNA technique resulted in increased susceptibility to apoptosis leading to the death of tumor cells. Therefore, our results suggest that one can use therapeutic agents which can down regulate the expression of fusion proteins in combination with chemotherapeutic agents as an effective treatment for these human solid tumors and leukemias.
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PMID:Inhibition of apoptosis by normal and aberrant Fli-1 and erg proteins involved in human solid tumors and leukemias. 917 86


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