Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human proenkephalin gene transcription is transactivated by human T-cell leukemia virus type I (HTLV-I) Tax in human Jurkat T lymphocytes. This transactivation was further enhanced in Jurkat cells treated with concanavalin A, cyclic AMP, or 12-O-tetradecanoylphorbol-13-acetate. Deletion and cis-element transfer analyses of the human proenkephalin promoter identified a cyclic AMP-responsive AP-1 element (-92 to -86) as both necessary and sufficient to confer Tax-dependent transactivation. Different AP-1 or cyclic AMP-responsive element-binding protein (CREB)/activating transcription factor (ATF) proteins which bind this element were expressed in murine teratocarcinoma F9 cells to identify those capable of mediating Tax-dependent transactivation of human proenkephalin gene transcription. Although CREB, c-Fos, c-Jun, and JunD did not have significant effects, JunB inhibited the Tax-dependent transactivation. In contrast, ATF3 dramatically induced Tax-dependent transactivation, which was further enhanced by protein kinase A. Electrophoretic mobility shift assays with recombinant fusion proteins expressed and purified from bacteria indicate that the DNA-binding activity of ATF3 is also dramatically enhanced by Tax. Chimeric fusion proteins consisting of the DNA-binding domain of the yeast transcription factor Gal4 and the amino-terminal domain (residues 1 to 66) of ATF3 were able to mediate Tax-dependent transactivation of a Gal4-responsive promoter, which suggests a direct involvement of this region of ATF3. Recombinant fusion proteins of glutathione S-transferase with either the amino- or carboxy-terminal (residues 139 to 181) domain of ATF3 were able to specifically interact with Tax. Furthermore, specific antisera directed against Tax coimmunoprecipitated ATF3 only in the presence of Tax.
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PMID:Novel interactions between human T-cell leukemia virus type I Tax and activating transcription factor 3 at a cyclic AMP-responsive element. 800 91

ATF3 gene, which encodes a member of the activating transcription factor/cAMP responsive element binding protein (ATF/CREB) family of transcription factors, is induced by many physiological stresses. As a step toward understanding the induction mechanisms, we isolated the human ATF3 gene and analyzed its genome organization and 5'-flanking region. We found that the human ATF3 mRNA is derived from four exons distributed over 15 kilobases. Sequence analysis of the 5'-flanking region revealed a consensus TATA box and a number of transcription factor binding sites including the AP-1, ATF/CRE, NF-kappa B, E2F, and Myc/Max binding sites. As another approach to understanding the mechanisms by which the ATF3 gene is induced by stress signals, we studied the regulation of the ATF3 gene in tissue culture cells by anisomycin, an approach that has been used to study the stress responses in tissue culture cells. We showed that anisomycin at a low concentration activates the ATF3 promoter and stabilizes the ATF3 mRNA. Significantly, co-transfection of DNAs expressing ATF2 and c-Jun activates the ATF3 promoter. A possible mechanism implicating the C-Jun NH2-terminal kinase/stress-activated protein kinase (JNK/SAPK) stress-inducible signaling pathway in the induction of the ATF3 gene is discussed.
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PMID:ATF3 gene. Genomic organization, promoter, and regulation. 857 71

In this report we investigate the molecular mechanisms that contribute to tissue damage following ischemia and ischemia coupled with reperfusion (ischemia/reperfusion) in the rat heart and kidney. We observe the activation of three stress-inducible mitogen-activated protein (MAP) kinases in these tissues: p38 MAP kinase and the 46- and 55-kDa isoforms of Jun N-terminal kinase (JNK46 and JNK55). The heart and kidney show distinct time courses in the activation of p38 MAP kinase during ischemia but no activation of either JNK46 or JNK55. These two tissues also respond differently to ischemia/reperfusion. In the heart we observe activation of JNK55 and p38 MAP kinase, whereas in the kidney all three kinases are active. We also examined the expression pattern of two stress-responsive genes, c-Jun and ATF3. Our results indicate that in the heart both genes are induced by ischemia and ischemia/reperfusion. However, in the kidney c-Jun and ATF3 expression is induced only by ischemia/reperfusion. To correlate these molecular events with tissue damage we examined DNA laddering, a common marker of apoptosis. A significant increase in DNA laddering was evident in both heart and kidney following ischemia/reperfusion and correlated with the pattern of kinase activation, supporting a link between stress kinase activation and apoptotic cell death in these tissues.
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PMID:Tissue-specific pattern of stress kinase activation in ischemic/reperfused heart and kidney. 924 62

We have previously identified a 20-bp sequence that mediates induced transcription in response to EGF, Ras, and Raf but not after TPA or UV stimulation. This composite response element, present in a long terminal repeat of a member within the VL30 family of retrotransposons, contains an AP-1-like site that cooperates in function with a juxtaposed sequence unrelated to known transcription factor-binding sites. Using in vitro translated proteins, we here demonstrate that the AP-1-like site preferentially binds ATF3/c-Jun and ATF3/JunD heterodimers. Results from a functional analysis indicate that the ATF3/c-Jun heterodimer, together with factors interacting with the 3' element, are most likely the important mediators of the response because overexpression of JunD, alone or in combination with ATF3, abolishes Ras-induced transcription. Partial purification by phosphocellulose and DNA-affinity chromatography in combination with Southwestern analyses reveals a 52-kDa protein that specifically binds to the sequence juxtaposed to the AP-1-like site. Scatchard analyses show that this sequence, TTAGTTAC, forms two different complexes with K(d)s of 1.9 x 10(-10) and 2.3 x 10(-9) M, respectively. Together, these results suggest that EGF/Ras/Raf induces transcription via combined activation of ATF3/c-Jun and a 52-kDa nuclear factor, whereas JunD acts as a repressor of this response.
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PMID:Characterization of a nuclear factor that binds juxtaposed with ATF3/Jun on a composite response element specifically mediating induced transcription in response to an epidermal growth factor/Ras/Raf signaling pathway. 926

Activating transcription factor (ATF) 3 is a member of ATF/cyclic adenosine monophosphate (cAMP)-responsive element binding protein (ATF/CREB) family of transcription factors and functions as a stress-inducible transcriptional repressor. To understand the stress-induced gene regulation by homocysteine, we investigated activation of the ATF3 gene in human endothelial cells. Homocysteine caused a rapid induction of ATF3 at the transcriptional level. This induction was preceded by a rapid and sustained activation of c-Jun NH(2)-terminal kinase/stress-activated protein kinase (JNK/SAPK), and dominant negative mitogen-activated protein kinase kinase 4 and 7 abolished these effects. The effect of homocysteine appeared to be specific, because cysteine or homocystine had no appreciable effect, but it was mimicked by dithiothreitol and beta-mercaptoethanol as well as tunicamycin. The homocysteine effect was not inhibited by an active oxygen scavenger. Deletion analysis of the 5' flanking sequence of the ATF3 gene promoter revealed that one of the major elements responsible for the induction by homocysteine is an ATF/cAMP responsive element (CRE) located at -92 to -85 relative to the transcriptional start site. Gel shift, immunoprecipitation, and cotransfection assays demonstrated that a complex (or complexes) containing ATF2, c-Jun, and ATF3 increased binding to the ATF/CRE site in the homocysteine-treated cells and activated the ATF3 gene expression, while ATF3 appeared to repress its own promoter. These data together suggested a novel pathway by which homocysteine causes the activation of JNK/SAPK and subsequent ATF3 expression through its reductive stress. Activation of JNK/SAPK and ATF3 expression in response to homocysteine may have a functional role in homocysteinemia-associated endothelial dysfunction.
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PMID:Homocysteine-responsive ATF3 gene expression in human vascular endothelial cells: activation of c-Jun NH(2)-terminal kinase and promoter response element. 1097 59

Endothelial cell injury underlies an increased occurrence of thromboembolic vascular disease in hereditary hyperhomocysteinemia. We have previously shown that homocysteine causes activation of c-Jun NH(2)-terminal kinase (JNK) and activating transcription factor 3/liver regenerating factor 1 (ATF3/LRF1) and induces apoptosis in human umbilical vein endothelial cells (HUVECs). In this study, the activation of JNK and ATF3 in HUVECs was mediated by the endoplasmic reticulum (ER) resident transmembrane kinase IRE1alpha and beta, which sense and transduce signal of the accumulationj of unfolded proteins in the ER. Moreover, dominant negative mutants of tumor necrosis factor receptor-associated factor 2 and mitogen-activated kinase kinase 4 and 7, as well as antisense ATF3 cDNA, inhibited cell death by homocysteine. These results indicate that the activation of JNK and ATF3 through the ER stress of homocysteine plays a role in the homocysteine-induced cell death. The JNK-ATF3 pathway may be implicated in endothelial cell injury associated with hereditary hyperhomocysteinemia.
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PMID:Activation of JNK and transcriptional repressor ATF3/LRF1 through the IRE1/TRAF2 pathway is implicated in human vascular endothelial cell death by homocysteine. 1172 7

Activating transcription factor (ATF) 3, a member of the ATF/cyclic adenosine monophosphate (cAMP)-responsive element binding protein (ATF/CREB) family of transcription factors, is induced by a wide range of stress stimuli. Although the ATF3 homodimer is known to repress transcription of several genes, its precise biological roles are still unclear. In this study, we investigated the functional role of ATF3 in doxorubicin (DOX=adriamycin)-treated neonatal rat cardiac myocytes. DOX rapidly activated JNK and c-Jun and induced ATF3 at both mRNA and protein level. Adenovirus-mediated expression of ATF3 protected cardiomyocytes from DOX-induced apoptosis, as determined by flow cytometry, cell viability, and TUNEL assay. It was further shown that p53, one of the apoptosis-inducing transcription factors, was downregulated in the ATF3-overexpressing cardiomyocytes. These results strongly suggest that ATF3 may function as a cytoprotective transcription factor in DOX-treated cardiac myocytes, at least in part, owing to downregulation of p53. ATF3 may be a novel therapeutic target that protects cardiac myocytes from DOX-induced apoptosis.
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PMID:ATF3 inhibits doxorubicin-induced apoptosis in cardiac myocytes: a novel cardioprotective role of ATF3. 1239 99

The mechanism of heme oxygenase-1 gene (ho-1) activation by heme in immortalized rat proximal tubular epithelial cells was examined. Analysis of the ho-1 promoter identified the heme-responsive sequences as the stress-response element (StRE), multiple copies of which are present in two enhancer regions, E1 and E2. Electrophoretic mobility shift assays identified Nrf2, MafG, ATF3, and Jun and Fos family members as StRE-binding proteins; binding of Nrf2, MafG, and ATF3 was increased in response to heme. Dominant-negative mutants of Nrf2 and Maf, but not of c-Fos and c-Jun, inhibited basal and heme-induced expression of an E1-controlled luciferase gene. Heme did not affect the transcription activity of Nrf2, dimerization between Nrf2 and MafG, or the level of MafG, but did stimulate expression of Nrf2. Heme did not influence the level of Nrf2 mRNA but increased the half-life of Nrf2 protein from approximately 10 min to nearly 110 min. These results indicate that heme promotes stabilization of Nrf2, leading to accumulation of Nrf2. MafG dimers that bind to StREs to activate the ho-1 gene.
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PMID:Heme activates the heme oxygenase-1 gene in renal epithelial cells by stabilizing Nrf2. 1245 73

Exposure of human cells to genotoxic agents induces various signaling pathways involved in the execution of stress- and DNA-damage responses. Inappropriate functioning of the DNA-damage response to ionizing radiation (IR) is associated with the human diseases ataxia-telangiectasia (A-T) and Nijmegen Breakage syndrome (NBS). Here, we show that IR efficiently induces Jun/ATF transcription factor activity in normal human diploid fibroblasts, but not in fibroblasts derived from A-T and NBS patients. IR was found to enhance the expression of c-Jun and, in particular, ATF3, but, in contrast to various other stress stimuli, did not induce the expression of c-Fos. Using specific inhibitors, we found that the ATM- and Nibrin1-dependent activation of ATF3 does neither require p53 nor reactive oxygen species, but is dependent on the p38 and JNK MAPkinases. Via these kinases, IR activates ATF-2, one of the transcription factors acting on the atf3 promoter. The activation of ATF-2 by IR resembles ATF-2 activation by certain growth factors, since IR mainly induced the second step of ATF-2 phosphorylation via the stress-inducible MAPkinases, phosphorylation of Thr69. As IR does not enhance ATF-2 phosphorylation in ATM and Nibrin1-deficient cells, both ATF-2 and ATF3 seem to play an important role in the protective response of human cells to IR.
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PMID:Induction of ATF3 by ionizing radiation is mediated via a signaling pathway that includes ATM, Nibrin1, stress-induced MAPkinases and ATF-2. 1283 46

The AP-1 transcription factor c-Jun is induced in axotomized neurons of the peripheral and central nervous systems, and in both cases upregulation of c-Jun expression has been correlated with axonal regeneration. More recently there has been interest in the c-Jun-related bZIP transcription factor, ATF3, and its function in neurons. ATF3 is also induced in nerve cells in response to axotomy and there is a correlation between increased ATF3 expression and upregulation of c-Jun in surviving neurons. Moreover, c-Jun is able to induce expression of ATF3. We investigated the effect of co-expressing c-Jun and ATF3 in two neuronal-like cell lines to model transcriptional events occurring in axotomized neurons undergoing regeneration. We show that expression of ATF3 with c-Jun significantly enhances c-Jun-mediated neurite sprouting, and that this phenotype is most likely mediated by a physical association of these two transcription factors. Our results suggest that a program of axonal regeneration is initiated when both c-Jun and ATF3 are upregulated in neurons in response to axotomy.
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PMID:ATF3 enhances c-Jun-mediated neurite sprouting. 1466 75


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