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

The consensus recognition element for the mammalian transcription factor AP-1 is very similar to that of the transcriptional activator GCN4. Here, we show that the AP-1 recognition element (ARE) found in the SV40 enhancer can activate transcription from a heterologous promoter in S. cerevisiae. This activation, however, is not dependent on the presence of GCN4 as evidenced by ARE-dependent transcription in a gcn4 yeast strain. A previously unknown yeast transcription factor that is probably responsible for this activation was identified and highly purified. The yeast factor, designated yAP-1, shares remarkably similar biochemical and DNA-binding characteristics with mammalian AP-1. These data suggest that the yeast and mammalian AP-1 are evolutionarily conserved and perhaps functionally related. Also note-worthy is that GCN4 can bind to a GCN4 recognition element (GCRE) and to the ARE with approximately equal affinities; yAP-1, however, has a much lower affinity for the GCRE than the ARE, suggesting that yAP-1 can discriminate between these elements in vivo.
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PMID:Transcriptional activation by the SV40 AP-1 recognition element in yeast is mediated by a factor similar to AP-1 that is distinct from GCN4. 283 68

Proto-oncogenes encode proteins with three main sites of action: the cell-surface membrane, the cytoplasm and the nucleus. Although the exact biochemical function of most proto-oncogene products is not understood, several of them are known to be involved in signal transduction. A role in gene regulation through DNA binding has been suggested for a recently isolated member of the group of oncogenes acting at the nucleus, v-jun. The C-terminus of the putative v-jun-encoded protein is similar in sequence to the C-terminus of the yeast transcriptional activator GCN4 (refs 8, 9), which forms its minimal DNA-binding domain. GCN4 binds to specific sites whose consensus sequence is highly similar to the recognition sequence of the mammalian transcriptional activator AP-1 (refs 12, 13). Like GCN4, AP-1 binds to promoter elements of specific genes and activates their transcription. Because of the similarity between the recognition sites for GCN4 and AP-1, we examined the possibility that AP-1 could be the product of the c-jun proto-oncogene. The experimental results reported here indicate that the JUN oncoprotein is a sequence-specific transcriptional activator similar to AP-1.
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PMID:Oncogene jun encodes a sequence-specific trans-activator similar to AP-1. 334 53

Androgen receptor (AR) brings about a ligand-dependent inhibition of low-affinity neurotrophin receptor (p75) promoter constructs in cultured cells, with the greatest inhibition being achieved with a reporter gene containing 1050 nucleotides (nt) of the promoter. The receptor domain critical for trans-repression localizes to the same region (amino acids 147-296) as that mandatory for transactivation. In contrast to trans-activation, AR does not interact directly with specific DNA elements to elicit trans-repression of p75 promoter constructs, although an intact DNA-binding domain of the receptor is required for both actions. In a search for interacting partners, both extensively purified full-length AR and AR-DNA binding domain were found to inhibit c-Jun/AP-1 site interaction without themselves binding to the AP-1 element. Prior binding of c-Jun to the AP-1 element protected the complex from the receptor's interference. Repression was not mutual, as c-Jun did not inhibit AR-androgen response element interaction or trans-activation through an androgen response element-containing promoter. The 1050-nt-long p75 promoter sequence does not contain an AP-1 element; an AP-1-like site in the vector backbone mediates the trans-repression by the AR in recipient cells. Intriguingly, an AR form with a large N-terminal deletion (the delta 46-408 mutant) behaved as a transcriptional activator of the p75 promoter through a mechanism that was also independent of specific DNA binding. Collectively, these data indicate that, in a proper context, AR is able to elicit both transrepression and trans-activation without interacting directly with specific DNA elements. Sequences responsible for the down-regulation of p75 mRNA by androgens in vivo are, however, not located in the proximal 1050 nt of the p75 promoter.
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PMID:Androgen receptor-mediated transcriptional regulation in the absence of direct interaction with a specific DNA element. 747 76

The human hepatitis B virus (HBV) HBx protein is a small transcriptional activator that is essential for virus infection. HBx is thought to be involved in viral hepatocarcinogenesis because it promotes tumorigenesis in transgenic mice. HBx activates the RAS-RAF-mitogen-activated protein (MAP) kinase signaling cascade, through which it activates transcription factors AP-1 and NF-kappa B, and stimulates cell DNA synthesis. We show that HBx stimulates cell cycle progression, shortening the emergence of cells from quiescence (G0) and entry into S phase by at least 12 h, and accelerating transit through checkpoint controls at G0/G1 and G2/M. Compared with serum stimulation, HBx was found to strongly increase the rate and level of activation of the cyclin-dependent kinases CDK2 and CDC2, and their respective active association with cyclins E and A or cyclin B. HBx is also shown to override or greatly reduce serum dependence for cell cycle activation. Both HBx and serum were found to require activation of RAS to stimulate cell cycling, but only HBx could shorten checkpoint intervals. HBx therefore stimulates cell proliferation by activating RAS and a second unknown effector, which may be related to its reported ability to induce prolonged activation of JUN or to interact with cellular p53 protein. These data suggest a molecular mechanism by which HBx likely contributes to viral carcinogenesis. By deregulating checkpoint controls, HBx could participate in the selection of cells that are genetically unstable, some of which would accumulate unrepaired transforming mutations.
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PMID:Hepatitis B virus HBx protein deregulates cell cycle checkpoint controls. 747 68

Although oxidative stress is involved in many human diseases, little is known of its molecular basis in eukaryotes. In a genetic approach, S. cerevisiae was used to identify elements involved in oxidative stress. By using hydrogen peroxide as an agent for oxidative stress, 34 mutants were identified. All mutants were recessive and fell into 16 complementation groups (pos1 to pos16 for peroxide sensitivity). They corresponded to single mutations as shown by a 2:2 segregation pattern. Enzymes reportedly involved in oxidative stress, such as glucose-6-phosphate dehydrogenase, glutathione reductase, superoxide dismutase, as well as glutathione concentrations, were investigated in wild-type and mutant-cells. One complementation group lacked glucose-6-phosphate dehydrogenase and was shown to be allelic to the glucose-6-phosphate dehydrogenase structural gene ZWF1/MET19. In other mutants all enzymes supposedly involved in oxidative-stress resistance were still present. However, several mutants showed strongly elevated levels of glutathione reductase, gluconate-6-phosphate dehydrogenase and glucose-6-phosphate dehydrogenase. One complementation group, pos9, was highly sensitive to oxidative stress and revealed the same growth phenotype as the previously described yap1/par1 mutant coding for the yeast homologue of mammalian transcriptional activator protein, c-Jun, of the proto-oncogenic AP-1 complex. However, unlike par1 mutants, which showed diminished activities of oxidative-stress enzymes and glutathion level, the pos9 mutants did not reveal any such changes. In contrast to other recombinants between pos mutations and par1, the sensitivity did not further increase in par1 pos9 recombinants, which may indicate that both mutations belong to the same regulating circuit.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mutants of Saccharomyces cerevisiae sensitive to oxidative and osmotic stress. 758 28

The HBx protein of hepatitis B virus (HBV) is a transcriptional activator that is required for infection and may play an important role in HBV-associated hepatocarcinogenesis. Recently, we and others have shown that HBx stimulates the Ras-Raf-MAP kinase cascade, which leads to enhanced cell proliferation and the activation of transcription factors AP-1 and NF-kappa B. Other studies have shown that HBx can activate transcription by interacting directly with nuclear components of the transcription machinery. Therefore we examined the basis for the different reported activities of HBx. Here, we show that HBx is a complex protein, displaying independent activities in different intracellular locations. The intracellular distribution of HBx protein was first investigated using scanning confocal laser immunomicroscopy and by genetic studies. Our work has established that HBx expressed in cultured cells is found authentically in both the cytoplasm and the nucleus. HBx is not strongly associated with any intracellular structures, but some preferential accumulation was observed near the cell surface. Next, HBx variants were constructed containing a functional or mutant nuclear localization sequence. We show that when HBx is engineered to relocate exclusively to the nucleus, it no longer activates the Ras-Raf-MAP kinase cascade, nor does it activate transcription factors AP-1 and NF-kappa B. Surprisingly, nuclear HBx fully retains the ability to stimulate HBV enhancer I, which is activated independently of the Ras and protein kinase C pathways. Therefore HBx protein stimulates signal transduction pathways in the cytoplasm and transactivates transcription elements in the nucleus. Furthermore, SV40 T antigen is shown to induce the nuclear sequestration of HBx protein and to block its activation of NF-kappa B, demonstrating that HBx is regulated by proteins that alter its intracellular distribution. The conflicting functions of HBx protein in viral infection and possibly carcinoma may involve the regulation of its differential distribution in the cell.
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PMID:The hepatitis B virus HBx protein is a dual specificity cytoplasmic activator of Ras and nuclear activator of transcription factors. 758 4

Nuclear factor of activated T-cells (NFAT) is a transcriptional activator that binds to the interleukin-2 promoter and is believed to be responsible for T-cell-specific interleukin-2 gene expression. Here we demonstrate using electrophoretic mobility shift assays that nuclear NFAT can be induced in the rat basophilic leukemia (RBL-2H3) mast cell line and rat bone marrow-derived mast cells upon cross-linkage of the high affinity receptor (Fc epsilon RI) for immunoglobulin E (IgE). Receptor-dependent activation of NFAT was mimicked by the combination of the protein kinase C activator phorbol myristate acetate and the calcium ionophore ionomycin. The induced binding activity was specific for the NFAT recognition motif because competition with nonradioactive NFAT oligonucleotide abolished the DNA binding activity, whereas nonradioactive oligonucleotides recognized by the transcription factors NF kappa B, glucocorticoid receptors, and TFIID did not. An oligonucleotide representing the AP-1 recognition sequence also blocked the NFAT DNA binding activity, as did a combination of anti-Fos and anti-Jun antibodies. Using electrophoretic mobility shift assays, AP-1-binding proteins were found to be induced in RBL-2H3 cells under the same conditions as was the NFAT binding activity. Together these data suggest that the NFAT complex in mast cells contains Fos and Jun proteins as does NFAT in T-cells. The appearance of nuclear NFAT binding activity was dependent in part upon calcium mobilization, as buffering the antigen-induced calcium rise with intracellular BAPTA strongly inhibited NFAT activation. Prevention of calcium influx with external EGTA also inhibited NFAT activation, indicating that release of calcium from internal stores was insufficient for sustained activation of mast cell NFAT. Cyclosporin A, a potent inhibitor of the calmodulin-dependent phosphatase calcineurin, blocked the induction of NFAT-DNA binding activity, implicating calcineurin as a key signaling enzyme in this pathway. These results suggest that NFAT is present in the mast cell line RBL-2H3 and in primary bone marrow-derived mast cells, is similar in subunit composition to the T-cell NFAT, and may play a role in calcium-dependent signal transduction in mast cells.
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PMID:Fc epsilon RI-mediated induction of nuclear factor of activated T-cells. 760 2

The Saccharomyces cerevisiae YAP2 gene encoding an AP-1-like transcriptional activator protein was cloned by selection for genes that confer pleiotropic drug resistance when present in high copy number. The novel YAP2 gene encodes a protein of 45827 daltons and is homologous in part to a known transcriptional activator protein encoded by YAP1/PDR4/SNQ3/PAR1. Homology was found only in both terminal regions. The N-terminal portion contains a region rich in basic amino acids, followed by a "leucine zipper" motif. Overexpression of YAP2 led to the induction of expression of an AP-1 recognition element (ARE)-dependent promoter. The yap1 disruptant has been shown to be sensitive to H2O2. In this study, we demonstrated that the yap1 disruptant is also unable to grow in medium containing 150 microM cadmium, whereas the yap2 disruptant exhibited no significant phenotypes. However, YAP2 in high copy number did suppress cadmium sensitivity, but not H2O2 sensitivity of the yap1 disruptant. YAP1 was able to mediate both cadmium- and H2O2-induced transcriptional activation of an ARE-dependent promoter. A high-copy-number plasmid bearing YAP2 mediated cadmium-induced transcriptional activation of this promoter. The inductions were prevented by the antioxidant N-acetyl-L-cysteine.
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PMID:Stress-induced transcriptional activation mediated by YAP1 and YAP2 genes that encode the Jun family of transcriptional activators in Saccharomyces cerevisiae. 810 71

AP-1 is a transcriptional activator composed of homo- and heterodimers of Jun and Fos proteins. It is involved in activation of genes, such as collagenase, stromelysin, IL-2 and TGF beta 1, by tumour promoters, growth factors and cytokines. AP-1 activity is also elevated in response to transforming oncogenes and is required for cell proliferation. AP-1 activity is subject to complex regulation both transcriptionally and post-transcriptionally. Transcriptional control of jun and fos gene expression determines the amount and composition of the AP-1 complex. The jun and fos genes are regulated both positively and negatively and are highly inducible in response to extracellular stimuli. Post translational control is also important. Both cJun and cFos are subject to regulated phosphorylation. In the case of cJun, phosphorylation of sites near the DNA-binding domain inhibits DNA-binding, while dephosphorylation reverses this inhibition. Phosphorylation of cJun on sites within the N-terminal activation domain increases its ability to activate transcription. The protein kinase phosphorylating these sites is stimulated by cytokines and growth factors. Another mechanism modulating AP-1 activity is transcriptional interference by members of the nuclear receptor family and is relevant for the pathophysiology of rheumatoid arthritis (RA). In RA, chronic inflammation leads to increased AP-1 activity in T cells,macrophages and synoviocytes as a response to secretion of cytokines such as IL-1 and TNF alpha. While the IL-2 gene plays a major role in T cell activation, another AP-1 target gene encodes an enzyme, collagenase, responsible for destruction of bone and tendon.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Various modes of gene regulation by nuclear receptors for steroid and thyroid hormones. 831 34

Nuclear factor of activated T cells (NFAT) is a transcriptional activator that binds to sequences in the interleukin-2 (IL-2) promoter and is thought to be largely responsible for the T cell-specific inducibility of IL-2 expression. Electrophoretic mobility shift assays (EMSA) showed that specific NFAT binding activity could also be induced in human B cells. The B cell NFAT complex, however, was not functional, since it failed to activate transcription from an NFAT-driven chloramphenicol acetyltransferase (CAT) construct. Competition with an AP-1 motif or with anti-Jun and anti-Fos antibodies abolished binding to the NFAT motif in both T and B cells, indicating that Jun and Fos are critical for NFAT complex formation in both cell types. Purified recombinant Jun and Fos proteins failed to bind directly to the NFAT motif. However, when combined with unstimulated B or T cell extracts, full-length, but not truncated, Jun/Fos heterodimers were able to form an NFAT complex, indicating the presence of a constitutively expressed nuclear factor(s) in B and T cells necessary for the formation of the NFAT complex in both cell types. An NFAT oligonucleotide carrying mutations in the 5' purine-rich part of the NFAT sequence failed to form a complex and to compete with the wild type motif for NFAT complex formation in both T and B cells. We therefore propose a model whereby a core NFAT complex consisting of Jun, Fos, and a constitutive nuclear factor is formed in both T and B cells, but an additional factor and/or post-translational modification of a factor, missing in B cells, might be required for transactivation by NFAT.
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PMID:Comparative analysis of NFAT (nuclear factor of activated T cells) complex in human T and B lymphocytes. 831 92


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