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)

The 'core' sequence is critical for efficient transcriptional activity of the SV40 enhancer. Moreover, the core was shown to be involved in a signal transduction pathway elicited by treatment of cells with phorbol ester tumor promoters. We report here the identification and characterization of activator protein-3 (AP-3), which recognizes the core element. AP-3 was purified to near homogeneity and identified as a 48K polypeptide. The purified protein is an efficient transcriptional activator in vitro. In addition, we show that AP-3 and a second factor that recognizes the SV40 enhancer, AP-2, interact in a mutually exclusive manner. These studies should facilitate understanding of the mechanism by which the SV40 enhancer achieves its characteristic broad cell-type specificity.
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PMID:Transcription factors AP-3 and AP-2 interact with the SV40 enhancer in a mutually exclusive manner. 254 45

The nucleotide sequence of the virG gene for a transcriptional activator on the agropine-type hairy-root-inducing plasmid pRiA4 was determined. The sequence contained one possible open reading frame. The gene product with a molecular size of 26.5 kDa was identified by an Escherichia coli coupled-transcription-translation system using cloned virG plasmids as templates. However, neither an ATG nor a GTG start codon which could give rise to such a protein was identified in the nucleotide sequence. Instead, TTG was found as a candidate for the start codon. This TTG was preceded, like most other TTG start codons, by both a Shine-Dalgarno (SD) sequence and a T signal which are respectively complementary to the 3'-end region of 16S rRNA and the T psi loop of initiator tRNA. Further evidence for the start at TTG was obtained by gene fusion experiments. When the E. coli lacZ gene, whose expression entirely depends on the transcription and translation from upstream regions, was connected in-phase with virG either directly upstream or downstream of the TTG sequence, only the latter fused gene expressed the beta-galactosidase activity in Agrobacterium cells in response to a plant phenolic compound, acetosyringone. The TTG codon preceded by an SD sequence and a T signal is also conserved in the virG sequences from other three tumor-inducing plasmids previously reported.
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PMID:Putative start codon TTG for the regulatory protein VirG of the hairy-root-inducing plasmid pRiA4. 267 Jun 79

Three human T-lymphotropic viruses have been isolated and characterized in the past 5 years. The ability to culture target cells with T-cell growth factor and sensitive detection systems for the virally encoded polymerase reverse transcriptase permitted isolation of HTLV-I, which is strongly linked to the cause of adult T-cell leukemia and associated with other lymphoid malignancies in endemic areas. The same techniques, using a permissive human tumor cell line, allowed the isolation and characterization of HTLV-III/lymphadenopathy-associated virus, which is implicated as the primary cause of the acquired immunodeficiency syndrome (AIDS). This virus shares some features with HTLV-I and HTLV-II, such as additional genes not found in most retroviruses. One gene codes for a transcriptional activator protein and may be a feature of a larger group of related retroviruses. The clear identification of the primary cause of AIDS has resulted in the development of specific immunologic reagents, preventive and therapeutic proposals, and comprehensive identification of the clinical diseases associated with this virus.
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PMID:A human T-lymphotropic retrovirus (HTLV-III) as the cause of the acquired immunodeficiency syndrome. 299 99

p53, the protein encoded by one of the most significant human tumor suppressor genes, is a sequence-specific transcriptional activator. When activated by a double-stranded DNA break, p53 function arrests cells in G1 and can induce apoptosis. Transcriptional activation function is critical for p53 tumor suppression, although transcriptional repressing and nontranscriptional functions of p53 may contribute. p53 activation requires that it bind to TFIID through interactions with TATA box-binding protein (TBP)-associated factors and potentially with TBP. Here, we studied the mechanism of p53 activation using in vitro transcription and a sufficiently high p53 concentration to squelch activated transcription. Squelching is thought to result when target molecules that interact with activation domains are titrated by binding to excess activator. Addition of either excess TFIIB or TFIID but not other proteins required for p53-activated transcription reversed squelching by high p53 concentrations, whereas neither stimulated transcription in reactions without excess p53. These results reveal that both TFIIB and TFIID are inhibited by high concentrations of p53 and suggest that p53 activation may work through direct or indirect interactions with both TFIIB and TFIID.
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PMID:Reversal of in vitro p53 squelching by both TFIIB and TFIID. 756 99

Expression of the gene encoding the mitochondrial fatty acid. beta-oxidation enzyme, medium-chain acyl-CoA dehydrogenase (MCAD), is regulated among tissues during development and in response to alterations in substrate availability. To identify and characterize cis-acting MCAD gene promoter regulatory elements and corresponding transcription factors, DNA-protein binding studies and mammalian cell transfection analyses were performed with hjman MCAD gene promoter fragments. DNA:protein binding studies with nuclear protein extracts prepared from hepatoma G2 cells, 3T3 fibroblasts, or Y-1 adrenal tumor cells identified three sequences (nuclear receptor response element 1 or NRRE-1, NRRE-2, and NRRE-3) that bind orphan members of the steroid/thyroid nuclear receptor superfamily including chicken ovalbumin upstream promoter transcription factor and steroidogenic factor 1. Sp1 binding sites (A-C) were identified in close proximity to each of the NRREs. NRRE-3 conferred cell line-specific transcriptional repression by interacting with chicken ovalbumin upstream promoter transcription factor or activation via steroidogenic factor 1. In contrast, the Sp1 binding site A behaved as a transcriptional activator in all cell lines examined. We propose that multiple nuclear receptor transcription factors interact with MCAD gene promoter elements to differentially regulate transcription among a variety of cell types.
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PMID:The human medium chain Acyl-CoA dehydrogenase gene promoter consists of a complex arrangement of nuclear receptor response elements and Sp1 binding sites. 759 84

The Interferon Regulatory Factors-1 and -2 (IRF-1 and IRF-2) play a transcriptional role in the regulation of the IFN-beta gene as well as other immunoregulatory genes. IRF-1 serves as a transcriptional activator whereas IRF-2 acts as an antagonistic transcriptional repressor. IRF-1 and IRF-2 also play opposing functional roles in cell growth regulation, and are implicated as a potential antioncogene and oncogene, respectively. To analyse the relationship between DNA binding/transcriptional repression and oncogenic transformation, NIH3T3 cells expressing C-terminal deletions of IRF-2 were established and assayed for transformation by saturation density analysis, anchorage independent growth in soft agar and tumor formation in nude mice. Cells expressing an IRF-2 protein of at least 160 N-terminal amino acids were transformed in vitro and tumorigenic in vivo, thus mapping IRF-2 oncogenic activity to its DNA binding/transcriptional repression domain. Overexpression of wild-type and truncated IRF-2 proteins resulted in reduced IFN-beta mRNA levels following induction by dsRNA. However, there was no effect of IRF-2 on IFN-beta inducibility by Sendai virus infection, suggesting the involvement of multiple IFN-beta induction pathways. In DNA binding assays, recombinant IRF-2 was found to preferentially bind to the IFN-beta PRDI site compared to IRF-1. These studies indicate that the transformed phenotype resulting from overexpression of IRF-2 may be due to constitutive engagement of the IRF-E recognition site, thus preventing DNA binding and transactivation of putative tumor suppressor genes by the IRF-1 anti-oncogene.
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PMID:Transcription factor IRF-2 exerts its oncogenic phenotype through the DNA binding/transcription repression domain. 763 Jun 38

The p53 tumor suppressor protein is a transcriptional activator, which can mediate apoptotic cell death in a variety of cell types. To determine whether sequence-specific trans-activation is a prerequisite for the induction of apoptosis by p53, the apoptotic effects of various p53 deletion mutants were monitored in an assay based on the transient transfection of HeLa cells. A truncated protein (p53dl214), containing only the first 214 amino-terminal residues of murine p53, induced extensive apoptosis, albeit at a slower rate than trans-activation-competent wild-type p53. p53dl214 also suppressed the transformation of rat fibroblasts by several oncogene combinations and particularly by myc plus ras and HPV E7 plus ras. p53dl214 lacks a major portion of the DNA-binding domain and cannot activate p53-responsive promoters. Moreover, a human p53 protein carrying mutations in residues 22 and 23 also triggered HeLa cell apoptosis, despite failing to induce significant activation of relevant p53 target promoters. These data suggest the existence of two p53-dependent apoptotic pathways--one requiring activation of specific target genes, and the other independent of sequence-specific trans-activation. The latter pathway may actually be totally uncoupled from the binding of p53 to its consensus DNA sites. The relative contribution of trans-activation-independent apoptosis to tumor suppression by p53 may be dictated by the specific genetic lesions present in the particular tumor.
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PMID:Induction of apoptosis in HeLa cells by trans-activation-deficient p53. 765 68

Phosphorylation of translation initiation factor 2 alpha is a highly conserved mechanism for down-regulating protein synthesis in response to starvation or stress. The yeast eIF-2 alpha kinase GCN2 is stimulated by deprivation for amino acids or purines. In addition to inhibiting general protein synthesis, GCN2 specifically stimulates translation of GCN4, a transcriptional activator of amino acid biosynthetic genes. HRI is an eIF-2 alpha kinase that is activated in rabbit reticulocytes by heme-deprivation and stress conditions that elicit the heat-shock response. The eIF-2 alpha kinase DAI is activated by double-stranded RNA during viral infections and is an important component of the interferon response. DAI has also been implicated as a tumor suppressor. These protein kinases provide an important means of coupling the rate of protein synthesis and cell division to environmental conditions.
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PMID:The eIF-2 alpha kinases: regulators of protein synthesis in starvation and stress. 771 Dec 90

Alterations in the tumor suppressor gene p53 are the most commonly identified changes in cancer, including neoplasia of the breast. The activity of p53 is regulated post-translationally. Phosphorylation state, subcellular localization, and interaction with any of a number of cellular proteins are likely to influence the function of p53. The exact effect of p53-mediated growth suppression seems to be cell-type specific but appears to be directly related to the ability of p53 to act as a specific transcriptional activator. The role that transcriptional repression plays in the function of WT p53 is less clear. It is also possible that p53 has a more direct activity in DNA replication and repair. Most documented p53 mutations result in single amino acid substitutions which may confer one or more of a spectrum of transforming abilities on the protein. Mutation may lead to nuclear accumulation of p53 protein; however, inactivation of p53 by nuclear exclusion and interaction with the mdm2 protein also appear to be important in tumorigenesis. Used in conjunction with other established factors, accumulation of cellular p53 may be a useful prognostic indicator in breast cancer. A syngeneic mouse model system yielded evidence that p53 mutations are important in the early, preneoplastic stages of mammary tumorigenesis. This murine system may provide the ability to investigate the functions of p53 in the early stages of breast cancer which are technically difficult to examine in the human system.
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PMID:Tumor suppressor p53 mutations and breast cancer: a critical analysis. 779 21

Alveolar rhabdomyosarcomas are pediatric solid tumors with a hallmark cytogenetic abnormality: translocation of chromosomes 2 and 13 [t(2;13) (q35;q14)]. The genes on each chromosome involved in this translocation have been identified as the transcription factor-encoding genes PAX3 and FKHR. The NH2-terminal paired box and homeodomain DNA-binding domains of PAX3 are fused in frame to COOH-terminal regions of the chromosome 13-derived FKHR gene, a novel member of the forkhead DNA-binding domain family. To determine the role of the fusion protein in transcriptional regulation and oncogenesis, we identified the PAX3-FKHR fusion protein and characterized its function(s) as a transcription factor relative to wild-type PAX3. Antisera specific to PAX3 and FKHR were developed and used to examine PAX3 and PAX3-FKHR expression in tumor cell lines. Sequential immunoprecipitations with anti-PAX3 and anti-FKHR sera demonstrated expression of a 97-kDa PAX3-FKHR fusion protein in the t(2;13)-positive rhabdomyosarcoma Rh30 cell line and verified that a single polypeptide contains epitopes derived from each protein. The PAX3-FKHR protein was localized to the nucleus in Rh30 cells, as was wild-type PAX3, in t(2;13)-negative A673 cells. In gel shift assays using a canonical PAX binding site (e5 sequence), we found that DNA binding of PAX3-FKHR was significantly impaired relative to that of PAX3 despite the two proteins having identical PAX DNA-binding domains. However, the PAX3-FKHR fusion protein was a much more potent transcriptional activator than PAX3 as determined by transient cotransfection assays using e5-CAT reporter plasmids. The PAX3-FKHR protein may function as an oncogenic transcription factor by enhanced activation of normal PAX3 target genes.
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PMID:The PAX3-FKHR fusion protein created by the t(2;13) translocation in alveolar rhabdomyosarcomas is a more potent transcriptional activator than PAX3. 786 45


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