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

Saccharomyces cerevisiae contains a group of transcription factors related to mammalian c-Jun. This yeast Jun-family of proteins consists of GCN4, a regulator of genes involved in amino acid biosynthesis, and yAP-1, a factor conferring pleiotropic drug resistance when overexpressed. In the work described here, we show that a third member of the yeast Jun-family exists. This protein has been designated CAD1 and provides resistance to cadmium when present on a high-copy plasmid. CAD1 and yAP-1 are related in their amino-terminal DNA binding domains and can recognize the same DNA target site in vitro. Overproduction of CAD1 leads to transcriptional activation of an artificial reporter gene in delta yap1 cells. High level production of either CAD1 or yAP-1 causes cells to acquire a pleiotropic drug-resistant phenotype and to be able to tolerate normally toxic levels of iron chelators and zinc. Surprisingly, disruption of the CAD1 gene has no effect on the normal cellular resistance to cadmium but delta yap1 mutants are hypersensitive to this cytotoxic metal. The cadmium hypersensitivity of the delta yap1 mutant described here indicates that one major role of YAP1 in the yeast cell is to mediate resistance to this metal.
 ...
PMID:Yeast bZip proteins mediate pleiotropic drug and metal resistance. 836 Jan 74

Effects of the carcinogenic metal cadmium on cellular calcium signalling and proto-oncogene expression were studied in mammalian cells. Cadmium ions interfered with bradykinin- and adenosinetriphosphate (ATP)-stimulated calcium transients in rat pheocromocytoma PC12 cells, but Cd2+ as such did not evoke intracellular Ca2+ spikes. At variance, cadmium ions caused a sustained elevation of intracellular free Ca2+ by inhibition of active calcium transport systems in various cell types. Problems of mutual interference of Ca2+ and Cd2+ analysis with the fluorescent probe Fura-2 could be overcome by the use of the fluorine 19 nuclear magnetic resonance (19F-NMR) probe acetoxymethyl ester of 1,2-bis(2-amino-5-fluorophenoxy)ethane-N,N,N'N'-tetraacetic acid (5F-BAPTA), which allows the measurement of free intracellular Ca2+, Cd2+ and other metal ions concurrently. Furthermore, the induction of the cellular protooncogenes c-fos and c-jun by Cd2+ was studied in PC12 cells. A dose of 0.5 microM Ca2+ sufficed to induce the c-Fos and c-Jun proteins within 30 min. These results support a model which suggests that cadmium stimulates cell proliferation by interference with intracellular calcium and induction of immediate early genes.
 ...
PMID:Effects of cadmium on cellular calcium and proto-oncogene expression. 890 21

We have shown previously that the heavy metal-responsive transcriptional activator MTF-1 regulates the basal and heavy metal-induced expression of metallothioneins. To investigate the physiological function of MTF-1, we generated null mutant mice by targeted gene disruption. Embryos lacking MTF-1 die in utero at approximately day 14 of gestation. They show impaired development of hepatocytes and, at later stages, liver decay and generalized edema. MTF-1(-/-) embryos fail to transcribe metallothionein I and II genes, and also show diminished transcripts of the gene which encodes the heavy-chain subunit of the gamma-glutamylcysteine synthetase, a key enzyme for glutathione biosynthesis. Metallothionein and glutathione are involved in heavy metal homeostasis and detoxification processes, such as scavenging reactive oxygen intermediates. Accordingly, primary mouse embryo fibroblasts lacking MTF-1 show increased susceptibility to the cytotoxic effects of cadmium or hydrogen peroxide. Thus, MTF-1 may help to control metal homeostasis and probably cellular redox state, especially during liver development. We also note that the MTF-1 null mutant phenotype bears some similarity to those of two other regulators of cellular stress response, namely c-Jun and NF-kappaB (p65/RelA).
 ...
PMID:Embryonic lethality and liver degeneration in mice lacking the metal-responsive transcriptional activator MTF-1. 958 78

The level of phosphorylated c-Jun NH2-terminal kinase (JNK) in LLC-PK1 cells treated with CdCl2 increased after 30 min and remained elevated even at 8 hr. And the activity of JNK assayed using glutathione S-transferase-c-Jun as substrate increased dose-dependently. Consistent with the JNK activation, marked increases in the levels of c-Jun and c-Jun phosphorylated on Ser63 and Ser73 were observed in cells treated with CdCl2. The pretreatment with an intracellular Ca2+ chelator, 1, 2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl) ester (BAPTA/AM), abolished cadmium-induced JNK phosphorylation. However, pretreatment with a cell permeable chelator of heavy metals, N,N,N', N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), did not. The present results showed that cadmium induces persistent activation of JNK pathway in a renal epithelial cell line, and that intracellular Ca2+ is necessary for the activation.
 ...
PMID:Activation of c-Jun NH2-terminal kinase (JNK/SAPK) in LLC-PK1 cells by cadmium. 979 7

Irradiation of mammalian cells with ultraviolet-B radiation (UV-B) triggers the activation of a group of stress-activated protein kinases known as c-Jun NH(2)-terminal kinases (JNKs). UV-B activates JNKs via UV-B-induced ribotoxic stress. Because oxidative stress also activates JNKs, we have addressed the question of whether the ribotoxic and the oxidative stress responses are mechanistically similar. The pro-oxidants sodium arsenite, cadmium chloride, and hydrogen peroxide activated JNK1 with slow kinetics, whereas UV-B potentiated the activity of JNK1 rapidly. N-acetyl cysteine (a scavenger of reactive oxygen intermediates) abolished the ability of all oxidative stressors tested to activate JNK1, but failed to affect the activation of JNK1 by UV-B or by another ribotoxic stressor, the antibiotic anisomycin. In contrast, emetine, an inhibitor of the ribotoxic stress response, was unable to inhibit the activation of JNK1 by oxidative stressors. Although UV-A and long wavelength UV-B are the spectral components of the ultraviolet solar radiation that cause significant oxidative damage to macromolecules, the use of a filter to eliminate the radiation output from wavelengths below 310 nm abolished the activation of JNK1 by UV. Our results are consistent with the notion that UV-B and oxidative stressors trigger the activation of JNK1 through different signal transduction pathways.
 ...
PMID:Different mechanisms of c-Jun NH(2)-terminal kinase-1 (JNK1) activation by ultraviolet-B radiation and by oxidative stressors. 1046 19

Stress response elements, which mediate induction of the mouse heme oxygenase-1 (HO-1) gene by several agents, resemble the binding site for the activator protein-1 (Jun/Fos), Maf, and Cap'n'Collar/basic leucine zipper (CNC-bZIP) families of proteins. In L929 fibroblasts, significant activation of an HO-1 enhancer-reporter fusion gene was observed only with the CNC-bZIP class of proteins with Nrf2 exhibiting the highest level of trans-activation, between 25- and 30-fold. To further examine the role of this factor in HO-1 gene regulation, a dominant-negative mutant, Nrf2M, was generated and conditionally expressed in L929 cells. The mutant protein was detected in cytoplasmic and nuclear fractions but did not affect cell growth. Under conditions of Nrf2M overexpression, HO-1 mRNA accumulation in response to heme, cadmium, zinc, arsenite, and tert-butylhydroquinone was inhibited by 85-95%. In contrast, overexpression of a dominant-negative mutant of c-Jun decreased L929 cell growth but did not inhibit HO-1 gene activation. Nrf2 does not homodimerize, but CNC-bZIP.small Maf protein heterodimers and Nrf2. Jun protein complexes are proposed to function as trans-activators. Co-expression of Jun proteins or p18, however, had no significant affect or inhibited Nrf2-mediated trans-activation. Taken together, these results implicate Nrf2 in the induction of the HO-1 gene but suggest that the Nrf2 partner in this function is a factor other than p18 or Jun proteins.
 ...
PMID:Nrf2, a Cap'n'Collar transcription factor, regulates induction of the heme oxygenase-1 gene. 1047 55

Cadmium is a toxic divalent cation that can initiate either mitogenic signals or apoptosis, possibly as a consequence of inducing different patterns of oncogene expression in different cells. We previously showed that Cd(2+) caused transcriptional activation of the c-fos protooncogene in mesangial cells (Wang and Templeton, J. Biol. Chem. 273, 73-79, 1998). The present study was undertaken to identify the signaling pathways that might be involved. Exposure to 10 microM CdCl(2) for 8 h caused a prolonged activation of Erk kinase and accumulation of c-fos mRNA. Inhibition of Erk activation with PD98059 only partially inhibited c-fos induction, indicating that additional pathways are involved. The c-Jun kinase/stress-activated protein kinase (SAPK) was also activated by Cd(2+). All three signals, i.e., Erk activity, SAPK activity, and c-fos mRNA levels in response to Cd(2+) showed a similar biphasic time course with an initial increase at 15-30 min and then a larger and more prolonged increase several hours later. Each signal also showed a similar concentration dependence, with less than 1 microM Cd(2+) causing the initial increase but values above 3 microM being required for the prolonged phase. These events showed high specificity for Cd(2+); other divalent metals tested under the same conditions (Mg(2+), Mn(2+), Co(2+), Ni(2+), Cu(2+), Zn(2+), and Hg(2+)) were without significant effects. We conclude that Cd(2+) is a specific inducer of c-fos in mesangial cells, probably through activation of both Erk kinase and SAPK pathways. The similar time and concentration dependence of the response of both pathways to Cd(2+) suggests a common basis for activation.
 ...
PMID:Activation of parallel mitogen-activated protein kinase cascades and induction of c-fos by cadmium. 1063 32

In response to various environmental stresses including heavy metals, the c-Jun N-terminal kinase (JNK) is phosphorylated and then it phosphorylates c-Jun protein. In the present study, effects of mercury chloride (HgCl2) on JNK signalling pathway were examined in LLC-PK1 cells. When exposed to 10 or 20 microM HgCl2, the level of phosphorylated JNK and the activity of JNK assayed in vitro using glutathione-S-transferase-c-Jun as substrate increased markedly. The level of phosphorylated JNK increased 30 min after HgCl2 exposure and remained elevated even at 8 h. On the other hand, no changes were found in the total amount of JNK protein. Consistent with the activation of JNK, c-Jun proteins phosphorylated on Ser63 and Ser73 were accumulated in cells exposed to HgCl2. Concomitantly, the levels of c-jun mRNA and c-Jun protein were elevated. When compared to other heavy metal compounds such as manganese chloride, zinc chloride, cadmium chloride, and lead chloride, HgCl2 could phosphorylate JNK more markedly. Neither intracellular Ca2+ nor sulfhydryl groups appeared to play a major role in the activation of JNK by HgCl2 exposure in this porcine renal epithelial cell line.
 ...
PMID:Mercury chloride activates c-Jun N-terminal kinase and induces c-jun expression in LLC-PK1 cells. 1069 84

The mouse heme oxygenase-1 (HO-1) gene, ho-1, contains two inducible enhancers, E1 and E2. Of several cell lines tested, induction of an E1/luciferase fusion construct, pE1-luc, by CdCl(2) is most pronounced in MCF-7 cells. In these cells, E1, but not E2, is necessary and sufficient for ho-1 gene activation. Exposure of MCF-7 cells to 10 micrometer CdCl(2) stimulates phosphorylation of ERK, JNK, and p38 mitogen-activated protein kinases, implicating one or more of these signaling pathways in ho-1 gene induction. SB203580, an inhibitor of p38, diminishes cadmium-stimulated pE1-luc expression and HO-1 mRNA levels by up to 70-80%. PD098059, an ERK pathway inhibitor, does not affect HO-1 mRNA induction at the highest concentration (40 micrometer) tested. Similarly, co-expression of a dominant-negative mutant of p38alpha, but not of ERK1, ERK2, JNK1, or JNK2, reduces basal and cadmium-induced pE1-luc activity. E1 contains binding sites for the activator protein-1 (Fos/Jun), Cap'n'Collar/basic leucine zipper (CNC-bZIP), and CCAAT/enhancer-binding protein (C/EBP) families of transcription factors. A dominant-negative mutant of Nrf2 (a CNC-bZIP member), but not of c-Jun or C/EBPbeta, inhibits pE1-luc activation by cadmium. Induction of the endogenous ho-1 gene is also inhibited by the Nrf2 mutant. Mutations of E1 that inhibit cadmium inducibility also suppress the trans-activation and DNA binding activities of Nrf2, and SB203580, but not PD098059, attenuates Nrf2-mediated trans-activation of pE1-luc. Taken together, these results indicate that cadmium induces ho-1 gene expression via sequential activation of the p38 kinase pathway and Nrf2.
 ...
PMID:Mechanism of heme oxygenase-1 gene activation by cadmium in MCF-7 mammary epithelial cells. Role of p38 kinase and Nrf2 transcription factor. 1087 44

Exposure of rat alveolar epithelial cells to 10 micromol/L CdCl2 causes time-dependent increases in steady-state mRNA levels of the gamma-glutamylcysteine synthetase catalytic (heavy) subunit (gamma-GCS) and of glutathione S-transferase isoforms (GST-alpha and GST-pi). The expression of gamma-GCS was significantly increased as early as 2 h after addition of cadmium. Maximal induction of gamma-GCS mRNA (approximately 4-fold), at 8 h, was subsequently followed by increases in gamma-GCS activity/protein and glutathione (GSH) levels. Maximal elevations in GST-pi (approximately 2-fold) and GST-alpha (approximately 10-fold) transcripts, at 8 and 24 h, respectively, were also accompanied by enhanced GST activity. Cadmium-induced oxidative stress, assessed by alterations in GSH homeostasis and an accelerated rate of intracellular oxidant production, could constitute early events in the signal transduction pathway mediating these responses. The dimeric transcription factor, activator protein-1 (AP-1), may also play a regulatory role in this process. This association is suggested by transcriptional activation of the immediate-early response genes, c-fos and c-jun, within 15 min after exposure to cadmium and by the enhancement of AP-1 DNA binding activity, involving a c-Jun protein complex, which is maximally induced (approximately 4-fold) by 2 h. These molecular changes likely function together to protect alveolar epithelial cells against cadmium toxicity.
 ...
PMID:Cadmium-mediated oxidative stress in alveolar epithelial cells induces the expression of gamma-glutamylcysteine synthetase catalytic subunit and glutathione S-transferase alpha and pi isoforms: potential role of activator protein-1. 1125 61


1 2 3 4 5 Next >>