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)

c-Jun NH2-terminal protein kinase (JNK), a member of the mitogen-activated protein kinase family, is activated in response to many stressful stimuli including heat shock, UV irradiation, protein synthesis inhibitors, and inflammatory cytokines. In this study, we investigated whether JNK plays a role in the cellular response to different drugs commonly used in cancer chemotherapy. Treatment of human KB-3 carcinoma cells with Adriamycin resulted in a time- and dose-dependent activation of JNK of up to 40-fold. Treatment with vinblastine or etoposide (VP-16) also activated JNK, with maximum increases of 6.5- and 4.3-fold, respectively. Consistent with these findings, increased c-Jun phosphorylation was observed after drug treatment of cells. In contrast, none of the drugs significantly activated the extracellular response kinase/mitogen-activated protein kinase pathway. Since these drugs are transport substrates for the MDR1 gene product, P-glycoprotein, JNK was assayed in two multidrug-resistant (MDR) KB cell lines, KB-A1 and KB-V1, selected for resistance to Adriamycin and vinblastine, respectively. Relative to KB-3 cells, basal JNK activity was increased 7-fold in KB-A1 cells and 4-fold in KB-V1 cells, with no change in JNK protein expression, indicating that JNK is present in a more highly activated form in the MDR cell lines. Under conditions optimal for JNK activation, Adriamycin, vinblastine, and VP-16 all induced MDR1 mRNA expression in KB-3 cells. Our findings suggest that JNK activation is an important component of the cellular response to several structurally and functionally distinct anticancer drugs and may also play a role in the MDR phenotype.
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PMID:Role of the stress-activated/c-Jun NH2-terminal protein kinase pathway in the cellular response to adriamycin and other chemotherapeutic drugs. 894 82

In response to cellular stress, the activation of the JNK cascade mediates phosphorylation of c-Jun that promotes its transactivation, which in turn activates the transcription of specific genes. In an experimental model of neuronal stress in vivo, by means of immunofluorescence and kinase assays we have found a reversible activation of JNK induced by the administration of the anti-cancer drug Adriamycin. In control neurons, a considerable basal level of the active, phosphorylated JNK was detected in neuronal nuclei, with a speckled distribution in addition to a diffuse nucleoplasmic signal. Adriamycin-induced neuronal stress was associated with a notable increase of this nuclear immunostaining, indicating activation of the JNK pathway which was confirmed by the increase of JNK enzymatic activity, while no changes in the total JNK were detected by Western blots. The JNK neuronal response to stress was also accompanied by an increase in the nuclear immunoreactivity for c-Jun and also by the de novo appearance of a strong nuclear phospho-c-Jun signal. These effects tend to revert to the control situation after 24 h of Adriamycin treatment. The nuclear compartmentalization of phospho-JNK and its substrate c-Jun was analyzed by confocal laser microscopy. Phospho-JNK strongly colocalizes with snRNPs in nuclear speckles, while the former was not concentrated in the coiled bodies. Upon stress induction, both c-Jun and phospho-c-Jun show a nucleoplasmic distribution in euchromatin domains, with the nucleoli free of immunolabeling. Furthermore, the nuclear speckles enriched in phospho-JNK exhibit a very low or undetectable signal with both c-Jun antibodies. Immunogold electron microscopy confirms the accumulation of phospho-JNK in interchromatin granule clusters (nuclear speckles), while in the nucleoplasm this kinase is mainly localized in perichromatin fibrils. Both c-Jun and phospho-c-Jun were also detected in perichromatin fibrils. Double labeling experiments show the colocalization of phospho-JNK and phospho-c-Jun in certain perichromatin fibrils. These results indicate that the neuronal response to the Adriamycin-induced stress is mediated by the activation of the JNK pathway. The accumulation of phospho-JNK in nuclear speckles raises the possibility that this kinase may be involved in the phosphorylation of an unknown splicing factor. Moreover, the colocalization of phospho-JNK and c-Jun in perichromatin fibrils, which are associated with sites of active transcription, suggests that these nuclear structures may be putative sites for the phosphorylation of JNK substrates.
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PMID:Stress-induced activation of c-Jun N-terminal kinase in sensory ganglion neurons: accumulation in nuclear domains enriched in splicing factors and distribution in perichromatin fibrils. 1073 65

Cardiac hypertrophy is an end point of chronic cardiac toxicity from a number of toxicants. Doxorubicin, cocaine, acetaldehyde, monocrotaline, and azide are examples of these toxicants, which may induce hypertrophy by increasing oxidants, circulating levels of catecholamines, and hemodynamic load or by inducing hypoxia. We summarize here the major signal transduction pathways and common changes in gene expression found with the classical hypertrophy inducers angiotensin II, endothelin 1, and catecholamines. Activation of G-proteins, calcium signaling, phosphoinositide 3-kinase (PI3K), certain family members of protein kinase Cs (PKCs), and three branches of mitogenactivated protein kinases (MAPKs), i.e. extracellular signal-regulated kinases (ERKs), p38, and c-Jun N-terminal kinases (JNKs), are important for developing a hypertrophic phenotype in cardiomyocytes. Characteristic changes of gene expression in hypertrophy include the elevated transcription of atrial natriuretic factor (ANF), beta-myosin heavy chain (beta MHC), skeletal alpha-actin (SkA), certain variants of integrins and perhaps tubulin genes, and reduced expression of the sarcoplasmic reticulum proteins phospholamban and sarco(endo)plasmic reticulum Ca2+-ATPase 2 alpha (SERCA2 alpha), and of the ryanodine receptors. Although which toxicants induce these molecular changes remains to be tested, increasing lines of evidence support that oxidants play a central role in cardiac hypertrophy. Oxidants activate small G-proteins, calcium signaling, PI3K, PKCs, and MAPKs. Oxidants cause cardiomyocytes to enlarge in vitro. Recent developments in transgenic, genomic, and proteomic technologies will provide needed tools to reveal the mechanism of chronic cardiac toxicity at the cellular and molecular levels.
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PMID:Molecular mechanisms of cardiac hypertrophy induced by toxicants. 1221 66

Pharmacologic induction of cancer cell differentiation has potential in the treatment of breast cancer. Doxorubicin, a widely used anthracycline antibiotic, was previously reported to induce differentiation of MCF-7 breast cancer cells. We demonstrate in this study that inhibition of MCF-7 breast cancer cell growth by low dose doxorubicin (0.01 microg/ml) was accompanied by an increase in cytokeratin 8/18 and milk fat globule membrane protein expression, biomarkers for differentiation of breast cancer, as well as an increase in JNK/SAPK phosphorylation. High dose doxorubicin (10.0 microg/ml) induced apoptosis in these cells. Overexpression of dominant-inhibitory forms of JNK1 and c-Jun blocked both the differentiation and apoptotic effects of doxorubicin. These results suggest that JNK/SAPK pathway signaling plays a prominent role in doxorubicin-induced cell cycle withdrawal, differentiation and control of apoptosis in this cell system. These findings support the possibility that JNK/SAPK pathway activation may be a means of therapeutic intervention in breast cancer.
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PMID:JNK/SAPK mediates doxorubicin-induced differentiation and apoptosis in MCF-7 breast cancer cells. 1284 16

Numerous signaling pathways were reported to be involved in the resistance for conventional cytotoxic drugs, although one of the main reasons is the overexpression of P-glycoprotein (P-gp) in multidrug resistant cancer cells. The overexpression of P-gp has been associated with the resistance to a wide range of anticancer drugs. Doxorubicin and paclitaxel are substrates of this transporter system and have an important role for the various human malignancies. In the present study, drug-sensitive MCF7 and multidrug resistant MCF7/ADR (characterized by overexpression of P-gp) human breast cancer cell lines were used as an experimental model. We have found that PS341 and MG132, proteasome inhibitors, reduced the degree of the multidrug resistance (MDR) in MCF7/ADR cells. This phenomenon was accompanied by a decrease in the IC50 value of doxorubicin and paclitaxel from 55.9 +/- 3.46 to 0.60 +/- 0.08 microM, and from 17.61 +/- 1.77 to 0.59 +/- 0.12 microM, respectively. The IC50 values of sensitive cells for doxorubicin and paclitaxel were about 0.42 and 0.83 microM, respectively. The effect of PS341 and MG132 on MCF7/ADR cells was associated with a significant decrease in both protein and gene levels of P-gp expression. Moreover, with regard to the expression of possible signal transduction pathways of mitogen-activated protein kinase (MAPK) related to the activation of mdr1, proteasome inhibitors did significantly influence the activation of these proteins. Western blot analysis revealed that 24 hr exposure of multidrug resistant MCF7/ADR cells with proteasome inhibitors did change the levels of DNA binding activity of nuclear factor-kappaB (NF-kappaB), pERK1/2, c-Jun, and p-c-Jun. In conclusion, we could remark that proteasome inhibitors (especially PS341) attenuate the resistance of MCF7/ADR cells for P-gp substrate drugs of doxorubicin and paclitaxel. Several proteins are supposed to be associated with the resensitization of the cells to conventional cytotoxic drugs, although decreased activity of P-gp is at least involved in the proteasome inhibitor-related resensitization. And influence with MAPK pathways, which have been reported to be associated with the regulation of P-gp, might be contributed to the resensitization brought by proteasome inhibitors.
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PMID:Proteasome inhibitors can alter the signaling pathways and attenuate the P-glycoprotein-mediated multidrug resistance. 1594 97

Protein kinase C (PKC) triggers cellular signals that regulate proliferation or death in a cell- and stimulus-specific manner. Although previous studies have demonstrated that activation of PKC with phorbol 12-myristate 13-acetate (PMA) protects cells from apoptosis induced by a number of mechanisms, including death receptor ligation, little is known about the effect or mechanism of PMA in the necrotic cell death. Here, we demonstrate that PMA-mediated activation of PKC protects against tumor necrosis factor (TNF)-induced necrosis by disrupting formation of the TNF receptor (TNFR)1 signaling complex. Pretreatment with PMA protected L929 cells from TNF-induced necrotic cell death in a PKC-dependent manner, but it did not protect against DNA-damaging agents, including doxorubicin (Adriamycin) and camptothecin. Analysis of the upstream signaling events affected by PMA revealed that it markedly inhibited the TNF-induced recruitment of TNFR1-associated death domain protein (TRADD) and receptor-interacting protein (RIP) to TNFR1, subsequently inhibiting TNF-induced activation of nuclear factor-kappaB and c-Jun NH2-terminal kinase (JNK). However, JNK inhibitors do not significantly affect TNF-induced necrosis, suggesting that the inhibition of JNK activation by PMA is not part of the antinecrotic mechanism. In addition, PMA acted as an antagonist of TNF-induced reactive oxygen species (ROS) production, thereby suppressing activation of ROS-mediated poly(ADP-ribose)polymerase (PARP), and thus inhibiting necrotic cell death. Furthermore, during TNF-induced necrosis, PARP was significantly activated in wild-type mouse embryonic fibroblast (MEF) cells but not in RIP-/- or TNFR-associated factor 2-/-MEF cells. Taken together, these results suggest that PKC activation ensures effective shutdown of the death receptor-mediated necrotic cell death pathway by modulating formation of the death receptor signaling complex.
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PMID:Phorbol 12-myristate 13-acetate protects against tumor necrosis factor (TNF)-induced necrotic cell death by modulating the recruitment of TNF receptor 1-associated death domain and receptor-interacting protein into the TNF receptor 1 signaling complex: Implication for the regulatory role of protein kinase C. 1679 36

Doxorubicin (DOX) is a potent anticancer drug, whose clinical use is limited on account of its toxicity. DOX cytotoxic effects have been associated with reactive oxygen species (ROS) generated during drug metabolism. ROS induce signaling cascades leading to changes in the phosphorylation status of target proteins, which are keys for cell survival or apoptosis. The mitogen-activated protein kinase (MAPK) cascades are routes activated in response to oxidative stress. In this work, the effects of DOX on cytotoxicity, indicators of oxidative stress (malondialdehyde -MDA- and GSH), and the phosphorylation status of extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases (JNKs), and p38 kinases were analyzed in primary cultures of rat hepatocytes. DOX (1-50 microM) did not modify lactate dehydrogenase (LDH) release into the medium, the levels of MDA (determined by high-performance liquid chromatography [HPLC]) or the intracellular GSH during the incubation time up to 6 h. GSH levels from mitochondria extracted by Percoll gradient from cultured hepatocytes were not modified by DOX, thus excluding its depletion or any impaired mitochondrial uptake. Characterization of proteins by Western blot analysis revealed that DOX increased phosphorylation of p38 kinases and JNK1 and JNK2 in a dose- and time-dependent manner. DOX also increased ERK2 phosphorylation at latter time points. In conclusion, DOX triggers activation of ERK, JNK, and p38 kinases in primary cultures of rat hepatocytes independently of oxidant damage.
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PMID:Doxorubicin-induced MAPK activation in hepatocyte cultures is independent of oxidant damage. 1738 85

The oncogene c-Jun has been found to be up-regulated in a variety of cancers, including osteosarcoma. Doxorubicin is a frontline chemotherapeutic against osteosarcoma, but is limited by toxicity. DNAzymes are oligonucleotides capable of specific catalysis of target mRNA. A biocompatible c-Jun DNAzyme nanoparticle formulated from chitosan regressed the growth and metastasis of pre-established tumors, especially in combination with doxorubicin. In vitro data confirmed that c-Jun knockdown chemosensitized these cells to doxorubicin treatment. c-Jun down-regulation-mediated tumor inhibition also led to concomitant decreased osteolysis. Clinically, knockdown of c-Jun with chitosan nanobiotechnology may proffer an improved treatment outcome for osteosarcoma.
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PMID:c-Jun knockdown sensitizes osteosarcoma to doxorubicin. 1864 1

Doxorubicin (Dox) has demonstrated potent activity in treating malignant lymphomas but its therapeutic efficacy is hampered by induction of cardiotoxicity. This side effect is related to the ability of the drug to generate reactive oxygen species in cells. Previously, we demonstrated that coupling Dox to penetratin (Pen), a cell penetrating peptide, represent a valuable strategy to overcome drug resistance in CHO cells. In the present study, we evaluated the consequences of the conjugation of Dox to Pen in term of apoptosis induction. When tested on CHO cells, Dox-Pen generated a typical apoptotic phenotype but at lower dose that needed for unconjugated Dox. Cell death induction was associated with chromatin condensation, caspase activation, Bax oligomerisation and release of cytochrome c. By using reactive oxygen species and c-jun NH2-terminal kinase (JNK) inhibitors, we prevented Dox- and Dox-Pen-induced CHO cell death. The chimeric soluble DR5 receptor that inhibits TRAIL induced cell death does not prevent Dox or Dox-Pen-induced cytotoxicity. These observations indicate that conjugation of Dox to cell penetrating peptide does not impair the ability of the drug to trigger cell death through activation of the intrinsic pathway involving c-Jun NH2-terminal kinase but could exhibit less toxic side effects and could warrant its use in clinic.
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PMID:Doxorubicin coupled to penetratin promotes apoptosis in CHO cells by a mechanism involving c-Jun NH2-terminal kinase. 2045 28

Doxorubicin (DOX) is a widely used anti-tumor agent. The clinical application of the medication is limited by its side effect which can elicit myocardial apoptosis and cardiac dysfunction. However, the underlying mechanism by which DOX causes cardiomyocyte apoptosis is not clear. The aim of present study is to investigate the role of high-mobility group box 1 (HMGB1) in DOX-induced myocardial injury, and signal pathway involved in regulation of HMGB1 expression in cardiomyocytes with DOX. We found treatment of isolated cardiomyocytes and naive mice with the DOX resulted in an increased HMGB1 expression which was associated with increased myocardial cell apoptosis. Pharmacological (A-box) or genetic blockade (TLR4 deficiency, TLR4(-/-)) of HMGB1 attenuated the DOX-induced myocardial apoptosis and cardiac dysfunction. In addition, our study showed that DOX resulted in an increment in the generation of peroxynitrite (ONOO(-)) and an elevation in phosphorylation of c-Jun N terminal kinase (JNK). Pretreatment of myocytes with FeTPPS, a peroxynitrite decomposition catalyst, prevented DOX-induced JNK phosphorylation, HMGB1 expression, myocardial apoptosis and cardiac dysfunction. Genetic (JNK(-/-)) or pharmacological (SP600125) inhibition of JNK ameliorated the DOX-induced HMGB1 expression and diminished myocardial apoptosis and cardiac dysfunction. Taken together, our results indicate that HMGB1 mediates the myocardial injury induced by DOX and ONOO(-)/JNK is a key regulatory pathway of myocardial HMGB1 expression induced by DOX.
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PMID:Role of HMGB1 in doxorubicin-induced myocardial apoptosis and its regulation pathway. 2252 57


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