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)

Tumors of glial origin such as glioblastoma multiforme (GBM) comprise the majority of human brain tumors. Patients with GBM have a very poor survival rate, with an average life expectancy of <1 year. We asked whether we could identify a survival pathway in high-grade glioma and oligodendroglioma cells that when suppressed, would induce apoptosis of these tumor cells but not of normal human adult astrocytes. To identify these pathways, we selectively suppressed the activity of a number of proteins (Ras, Rac1, Akt1, RhoA, c-jun, and MEK1/2) hypothesized to play roles in cell survival. We found that suppression of Rac1, a small GTP-binding protein, inhibited survival and produced apoptosis in three human glioma cell lines (U87, U343, and U373). Serum induced the activity of Rac1 and the activity or phosphorylation state of p21-activated kinase 1 and c-Jun NH(2)-terminal kinase (JNK), two intracellular targets of Rac1. Suppression of Rac1 also induced apoptosis in 19 of 21 short-term cultures of human primary cells from grades II and III oligodendroglioma and grade IV glioblastoma that varied in p53, epidermal growth factor receptor, epidermal growth factor receptor vIII, MDM2, and p16/p19 mutational or amplification status. In contrast, inhibition of Rac1 activity did not induce apoptosis of normal primary human adult astrocytes. In both established glioma cell lines and primary glioma cells, apoptosis induced by the inhibition of Rac was partially rescued by activated mitogen-activated protein kinase kinase 1, an activator of JNK, suggesting that JNK functions downstream of Rac1 in glioma cells. These results indicate that Rac1 regulates a major survival pathway in most glioma cells, and that suppression of Rac1 activity stimulates the death of virtually all glioma cells, regardless of their mutational status. Agents that suppress Rac1 activity may therefore be useful therapeutic treatments for malignant gliomas.
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PMID:Suppression of Rac activity induces apoptosis of human glioma cells but not normal human astrocytes. 1192 35

Several studies have shown that hexavalent chromium [Cr(VI)] induces apoptosis in a variety of in vitro test systems. We instilled intra-tracheally either saline or sodium dichromate (0.25 mg/kg body weight), for three consecutive days, to Sprague-Dawley rats. TUNEL analyses showed a marked increase of the apoptotic index in both bronchial epithelium and lung parenchyma of Cr(VI)-treated rats, but no effect was detected in their liver. In parallel, the expression of 13 out of 18 apoptosis-related genes, evaluated by cDNA array analysis, was significantly enhanced in rat lung. The overexpressed genes included c-Jun N-terminal kinases 1, 2 and 3, bcl-x, bcl-2-associated death promoter and bcl-2-related ovarian killer protein, caspases 1, 3 and 6, DNase I precursor, DNA topoisomerases I and II alpha, and poly(ADP-ribose) polymerase. The enhancement of p53 expression in the lung was borderline to statistical significance. Expressions of bcl-2, bax-alpha, mdm2 and DNA topoisomerase IIB were not enhanced to a significant extent in lung. No induction of gene expression was observed in rat liver. RT-PCR analyses confirmed that Cr(VI) enhances the expression of c-Jun N-terminal kinase 1, caspase 6, and DNase I precursor but not that of bcl-2 in lung, while none of these genes was overexpressed in the liver of Cr(VI)-treated rats. The lack of stimulation of apoptosis in the liver parallels the failure of Cr(VI) to produce genotoxic damage, as we previously observed under identical experimental conditions. These negative findings may be ascribed to reduction of Cr(VI) to Cr(III) when traveling from the respiratory tract to the liver. On the other hand, induction of apoptosis in the respiratory tract parallels the occurrence of genotoxic effects and oxidative DNA damage produced by Cr(VI) in the same tissue. As previously shown in another laboratory, Cr(VI) did not induce lung tumors after 30 months of administration of the same daily dose. Therefore, apoptosis is likely to provide a protective mechanism at a post-genotoxic stage of Cr(VI) carcinogenesis.
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PMID:Induction of apoptosis in the lung but not in the liver of rats receiving intra-tracheal instillations of chromium(VI). 1196 Sep 10

The destruction of dopaminergic and serotonergic nerve cells by selective 6-hydroxydopamine (6-OHDA), 5,6-dihydroxytryptamine (5,6-DHT) and 5,7-dihydroxytryptamine (5,7-DHT), respectively, is a commonly used tool to investigate the mapping of neuronal pathways, elucidation of function and to mimic human neurodegenerative disease such as Parkinson's and Alzheimer's diseases. Despite intense investigations, a complete picture of the precise molecular cascade leading to cell death in a single cellular model is still lacking. In this study, we provide evidence that 6-OHDA, 5,6- and 5,7-DHT toxins-induced apoptosis in peripheral blood lymphocytes cells in a concentration-dependent fashion by a common oxidative mechanism involving: (1) the oxidation of toxins into quinones and production of the by-product hydrogen peroxide, reflected by desipramine-a monoamine uptake blocker-and antioxidants inhibition, (2) activation and/or translocation of nuclear factor-kappaB, p53 and c-Jun transcription factors, showed by immunocytochemical diaminobenzidine-positive stained nuclei, (3) caspase-3 activation, reflected by caspase Ac-DEVD-CHO inhibition, (4) mRNA and protein synthesis de novo according to cycloheximide and actinomycin D cell death inhibition. These results are consistent with the notion that uptake and intracellular autoxidation of those toxins precede the apoptotic process and that once H(2)O(2) is generated, it is able to trigger a specific cell death signalisation. Thus, taken together these results, we present an ordered cascade of the major molecular events leading peripheral blood lymphocytes to apoptosis. These results may contribute to explain the importance of H(2)O(2) as a second messenger of death signal in some degenerative diseases linked to oxidative stress stimuli.
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PMID:Monoamine neurotoxins-induced apoptosis in lymphocytes by a common oxidative stress mechanism: involvement of hydrogen peroxide (H(2)O(2)), caspase-3, and nuclear factor kappa-B (NF-kappaB), p53, c-Jun transcription factors. 1199 35

Paclitaxel is able to cause cell death through the induction of apoptosis. Cell death characteristics for docetaxel have not yet been described in detail. We investigated four unselected human ovarian cancer cell lines for the sensitivity to a 1hr exposure to docetaxel and calculated the concentrations inhibiting 50% (IC(50)) and 90% (IC(90)) of cell growth. Of the cell lines A2780, H134, IGROV-1 (all wild-type p53) and OVCAR-3 (mutant, mt p53) A2780 was most sensitive and OVCAR-3 least sensitive. Equitoxic drug concentrations representing IC(90) values (25-510nM) were applied for 1hr to measure cell cycle distribution, DNA degradation, and to count apoptotic cell bodies and cells with multifragmented nuclei at various time-points after drug exposure. H134, IGROV-1 and OVCAR-3 showed a continued mitotic block up to at least 72hr and prolonged presence of cells with multifragmented nuclei. High percentages of apoptosis were calculated at 48hr and at later time-points. In contrast, A2780 cells accumulated in the S-phase of the cell cycle and apoptosis was hardly present. The changes in the expression levels of p53, p21/WAF1, Bax and Bcl-2, were not predictive for docetaxel-induced apoptosis. Caspase-3 activation occurred only in cells with accumulation in the G2/M phase starting as early as 8hr in OVCAR-3. Prolonged Bcl-2 phosphorylation was evident in OVCAR-3, visible at 24hr in H134 and IGROV-1, while this phenomenon did not occur in A2780. The mitogen-activated protein kinase pathway (JNKs/SAPKs or c-Jun N-terminal kinases/stress-activated protein kinases, JNK1/2; extracellular response kinase, ERK1/2; p38) did not seem to be directly involved in Bcl-2 phosphorylation or apoptosis. We conclude that docetaxel is able to activate caspase-3, induce Bcl-2 phosphorylation and apoptosis in cells that show a prolonged G2/M arrest, but cells may also die by a caspase-3-independent cell death mechanism.
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PMID:Variation in the kinetics of caspase-3 activation, Bcl-2 phosphorylation and apoptotic morphology in unselected human ovarian cancer cell lines as a response to docetaxel. 1199 42

Granulocytes and monocytes develop from a common myeloid progenitor. Early granulopoiesis requires the C/EBPalpha, PU.1, RAR, CBF, and c-Myb transcription factors, and terminal neutrophil differentiation is dependent upon C/EBPepsilon, PU.1, Sp1, CDP, and HoxA10. Monopoiesis can be induced by Maf-B, c-Jun, or Egr-1 and is dependent upon PU.1, Sp1, and ICSBP. Signals eminating from cytokine receptors modulate factor activities but do not determine cell fates. Orchestration of the myeloid developmental program is achieved via cooperative gene regulation, via synergistic and inhibitory protein-protein interactions, via promoter auto-regulation and cross-regulation, via regulation of factor levels, and via induction of cell cycle arrest: For example, c-Myb and C/EBPalpha cooperate to activate the mim-1 and NE promoters, PU.1, C/EBPalpha, and CBF, regulate the NE, MPO, and M-CSF Receptor genes. PU.1:GATA-1 interaction and C/EBP suppression of FOG transcription inhibits erythroid and megakaryocyte gene expression. c-Jun:PU.1, ICSBP:PU.1, and perhaps Maf:Jun complexes induce monocytic genes. PU.1 and C/EBPalpha activate their own promoters, C/EBPalpha rapidly induces PU.1 and C/EBPepsilon RNA expression, and RARalpha activates the C/EBPepsilon promoter. Higher levels of PU.1 are required for monopoiesis than for B-lymphopoiesis, and higher C/EBP levels may favor granulopoiesis over monopoiesis. CBF and c-Myb stimulate proliferation whereas C/EBPalpha induces a G1/S arrest; cell cycle arrest is required for terminal myelopoiesis, perhaps due to expression of p53 or hypo-phosphorylated Rb.
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PMID:Transcriptional regulation of granulocyte and monocyte development. 1203 76

Cellular response to oxidative stress is a complex process that is often connected to cell cycle regulation. The present study examines the effect of H(2)O(2) on cell cycle regulation and involvement of reactive oxygen species (ROS) in these H(2)O(2)-induced responses in a p53-deficient human lung carcinoma cell line, H1299. Treatment of the cells with H(2)O(2) caused a G2/M phase arrest. Among the redox-sensitive transcription factors, NF-kappaB and AP-1, we found that only AP-1 was activated by 200 microM H(2)O(2) in human lung cells. Furthermore, electrophoretic mobility shift assays revealed that H(2)O(2) enhanced the DNA binding of AP-1 to a putative AP-1 binding element (TGAGGAA) in the p21(WAF1/CIP1) promoter region (between -2203 and -2197 nucleotides upstream of the transcription initiation site). An increase in c-Jun phosphorylation by ERK was also found to accompany the increased AP-1 activity as detected by Western blot. PD98059, a specific inhibitor of MEK, diminished H(2)O(2)-induced phosphorylation of c-Jun and DNA binding activity of AP-1, decreased expression of p21(WAF1/CIP1), and released the cells from G2/M arrest. Taken together, these results revealed a novel AP-1 binding site in the promoter region of p21(WAF1/CIP1) and a possible cell cycle regulation mechanism mediated by activation of a redox-dependent ERK signaling pathway.
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PMID:H(2)O(2)-induced AP-1 activation and its effect on p21(WAF1/CIP1)-mediated G2/M arrest in a p53-deficient human lung cancer cell. 1205 10

Lithium, the major drug used to treat manic depressive illness, robustly protects cultured rat brain neurons from glutamate excitotoxicity mediated by N-methyl-D-aspartate (NMDA) receptors. The lithium neuroprotection against glutamate excitotoxiciy is long-lasting, requires long-term pretreatment and occurs at therapeutic concentrations of this drug. The neuroprotective mcchanisms involve inactivation of NMDA receptors, decreased expression of pro-apoptotic proteins, p53 and Bax, enhanced expression of the cytoprotective protein, Bcl-2, and activation of the cell survival kinase, Akt. In addition, lithium pretreatment suppresses glutamate-induced loss of the activities of Akt, cyclic AMP-response element binding protein (CREB), c-Jun - N-terminal kinase (JNK) and p38 kinase. Lithium also reduces brain damage in animal models of neurodegenerative diseases in which excitotoxicity has been implicated. In the rat model of stroke using middle cerebral artery occlusion, lithium markedly reduces neurologic deficits and decreases brain infarct volume even when administered after the onset of ischemia. In a rat Huntington's disease model, lithium significantly reduces brain lesions resulting from intrastriatal infusion of quinolinic acid, an excitotoxin. Our results suggest that lithium might have utility in the treatment of neurodegenerative disorders in addition to its common use for the treatment of bipolar depressive patients.
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PMID:Neuroprotective effects of lithium in cultured cells and animal models of diseases. 1207 10

The production of nitric oxide (NO) is an essential determinant in auto- and paracrine signaling. NO is generated under inflammatory conditions and may serve as a cytotoxic molecule to produce cell demise along an apoptotic or necrotic pathway. NO also gained attention as a regulator of immune function and a death inhibitor. Cytotoxicity because of substantial NO-formation is established to initiate apoptosis, characterized by upregulation of the tumor suppressor p53, changes in the expression of pro- and antiapoptotic Bcl-2 family members, cytochrome c relocation, activation of caspases, and DNA fragmentation. However, NO-toxicity is not a constant value and NO may protect several cell types from entering programmed cell death. Preactivation of macrophages with a nontoxic dose of S-nitrosoglutathione (200 microM) or lipopolysaccharide/interferon-gamma/N(G)-monomethyl-L-arginine for 15 hours attenuated death in response to various agonists, suppressed p53 accumulation, and abrogated caspase activation. Prestimulation of macrophages with cytokines or low-level NO activated the transcription factor NF-kappaB as well as AP-1 and promoted immediate early gene expression of cyclooxygenase-2 (COX-2). NF-kappaB activation comprised p50/p65-heterodimer formation, IkappaB degradation, and activation of a luciferase reporter construct, that contained four copies of the NF-kappaB-site derived from the murine COX-2 promoter. A NF-kappaB decoy approach (oligonucleotides directed against NF-kappaB) or transfection of a dominant-negative c-Jun mutant (TAM67) abrogated not only the COX-2 expression but also the inducible protection. Blocking NO- or cytokine-mediated inducible protection at the level of NF-kappaB and/or AP-1 restored the occurrence of apoptotic features. Our experiments underscore the role of COX-2 in attenuating natural occurring cell death (i.e., apoptosis).
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PMID:The role of nitric oxide and cyclooxygenase-2 in attenuating apoptosis. 1208 96

DNA damage, an important initiator of neuronal death, has been implicated in numerous neurodegenerative conditions. We previously delineated several pathways that control embryonic cortical neuronal death evoked by the DNA-damaging agent, camptothecin. In this model, the tumor suppressor p53 and cyclin-dependent kinases (CDKs) are activated independently and cooperate to mediate the conserved death pathway. To further our understanding, we presently examined whether the c-Jun/JNK pathway modulates death and whether this pathway is regulated by CDKs, p53, and Bax. We show that c-Jun/JNK is activated following DNA damage. Moreover, the c-Jun pathway is one mediator of death, because expression of dominant negative c-Jun and cdc42, and JNK pathway inhibitors are neuroprotective. Although previous evidences indicate that JNK3 is required for neuronal death under certain conditions, we show that JNK3 deficiency only partially mediates c-Jun phosphorylation and its deficiency does not protect neurons from death. Interestingly, we provide evidence that CDK activity regulates c-Jun but does not affect upstream pathways that lead to JNK phosphorylation. Finally, c-Jun activation is independent of p53 and Bax. Accordingly, we propose that c-Jun is regulated by the JNK and CDK pathways and that both must be activated for efficient c-Jun activation to occur.
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PMID:Interaction of the c-Jun/JNK pathway and cyclin-dependent kinases in death of embryonic cortical neurons evoked by DNA damage. 1209 88

Previous studies have suggested that p53 is required for apoptosis induction by phenethyl isothiocyanate (PEITC), which is a highly promising cancer chemopreventive agent. Here, we report that p53 is not required for PEITC-induced apoptosis in the PC-3 human prostate cancer cell line and that the PEITC-induced apoptosis is mediated by extracellular signal-regulated kinases (ERK1/2). Exposure of PC-3 cells to an apoptosis-inducing concentration of PEITC (10 microM) resulted in a rapid and sustained activation of ERK1/2 that was evident as early as 1 h after PEITC treatment and persisted for the duration of the experiment (24-h after PEITC exposure). The PEITC-mediated activation of ERK1/2 was associated with an increase in phosphorylation of its substrate Elk-1 at Ser383. The PEITC-induced activation of ERK1/2 as well as apoptosis was abolished in the presence of mitogen-activated protein/ERK kinase 1 (a kinase upstream of ERK1/2) inhibitor PD98059. Exposure of PC-3 cells to 10 microM PEITC also resulted in a time-dependent activation of p38 protein kinase that was associated with increased phosphorylation of activating transcription factor 2 at Thr71. Even though the PEITC-induced activation of p38 protein kinase was abrogated in the presence of its specific inhibitor SB202190, inhibition of p38 protein kinase activation did not prevent PEITC-induced apoptosis. In contrast to previous reports in other cellular systems, c-Jun NH(2)-terminal kinases were not activated by PEITC treatment in PC-3 human prostate carcinoma cell line. In conclusion, the results of the present study indicate that p53 is not essential for PEITC-induced apoptosis and that the PEITC-induced apoptosis in PC-3 human prostate carcinoma cell line is mediated by ERKs. Thus, it seems reasonable to postulate that PEITC may be effective against tumors with normal as well as mutant p53.
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PMID:Phenethyl isothiocyanate-induced apoptosis in p53-deficient PC-3 human prostate cancer cell line is mediated by extracellular signal-regulated kinases. 1209 62


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