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)

The literature provides strong precedent for both pro-tumorigenic and tumor suppressor roles for the c-Jun N-terminal kinases (JNKs) in the setting of oncogenesis. Clearly, JNKs are activated by numerous oncogenes and growth factors and the literature documents a role for these MAP kinases in cell proliferation and transformation. By contrast, JNKs mediate signals from diverse stimuli that result in cell death or differentiation and a role for JNKs as tumor suppressors has emerged. This enigmatic nature of the JNKs in the setting of oncogenesis is considered herein. Further illumination of the complex and context-dependent functions of the JNKs in cancer cells is of obvious importance for the rational use of small molecule JNK inhibitors as therapeutics.
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PMID:JNK regulation of oncogenesis. 1668 9

Erosive osteolysis induced by implant-derived wear debris is mediated by recruitment and activation of osteoclasts in a pro-inflammatory microenvironment that is enriched with osteoclastogenic and pro-inflammatory cytokines such as RANKL and tumor necrosis factor alpha (TNF-alpha). These cytokines activate the transcription factor NF-kappaB and MAP kinases, including c-Jun, Erks, and p38, all known to be essential for the development of osteoclasts. We have recently documented that TNF and RANKL play a pivotal role in the development of inflammatory osteolysis. We have also found that polymethyl methacrylate (PMMA) particles stimulate osteoclastogenesis, at least in part, by induction of RANKL, TNF, and by activation of NF-kappaB and MAP kinases. More importantly, our data indicate that inhibitors of NF-kappaB and the MAP kinases p38 and ERK abrogate particle-induced osteoclastogenesis. In the current study, we investigated if inhibition of c-Jun N-Terminal kinase (JNK) pathway alters PMMA-induced osteoclastogenesis. Our findings point out that PMMA particles activate the JNK pathway in wild-type and TLR4-null (endotoxin-resistant) osteoclast precursors. This activation was selectively blocked in a dose-dependent fashion by the JNK inhibitor SP600125. Most importantly, we provide evidence that SP600125 inhibits osteoclast formation in a reversible manner. Collectively, our findings demonstrate that activation of the JNK pathway is essential for basal and PMMA-stimulated osteoclastogenesis, and buttress the potential significance of targeting the JNK pathway to inhibit osteolysis.
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PMID:Map kinase c-JUN N-terminal kinase mediates PMMA induction of osteoclasts. 1673 13

We tested whether the protection of hypoxic neurons by the inhaled anesthetic isoflurane is related to the Ca2+-dependent phosphorylation of MAP kinases and anti-apoptotic co-factors. In cultures of mouse cortical neurons we measured changes in the phosphorylation of Ca2+-dependent and Ca2+-independent MAP kinases, transcription factors, and apoptosis regulators after hypoxia or hypoxia combined with isoflurane (1% in gas phase). In hypoxic neurons, isoflurane reduced cell death and TUNEL staining by >80%. Isoflurane released Ca2+ from intracellular stores, increasing [Ca2+]i in oxygenated neurons by approximately 20%. Neuroprotection was associated with a smaller increase in [Ca2+]i in hypoxic neurons and required IP3 receptors and phospholipase C. In hypoxic neurons, isoflurane increased the phosphorylation of the Ca2+-dependent MAP kinases Pyk2 and p42/44 (ERK). The Ca2+-independent MAP kinase p38 pathway showed increased phosphorylation with isoflurane but not with ionomycin, a Ca2+ ionophore. JNK was phosphorylated in hypoxic neurons in the presence of isoflurane, as was the transcription factor c-Jun; JNK inhibition with SP600125 prevented both phosphorylation of c-Jun and neuroprotection. Isoflurane decreased phosphorylation of the pro-apoptotic cofactors Bad and p90RSK and increased Akt phosphorylation. However, with the exception of c-Jun, transcription factors (Elk-1, GSK-3, Forkhead, p90RSK) decreased or remained unchanged. We conclude that isoflurane's protection of hypoxic cortical neurons involves signaling that includes changes in intracellular Ca2+ regulation, several MAP kinase pathways and modulation of apoptosis regulators.
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PMID:The inhaled anesthetic, isoflurane, enhances Ca2+-dependent survival signaling in cortical neurons and modulates MAP kinases, apoptosis proteins and transcription factors during hypoxia. 1686 27

Epidermal growth factor receptor (EGFR) is a critical mediator of several types of epithelial cancers. Skin cancer arising from exposure to ultraviolet B irradiation (UVB) from the sun is a prominent form of human cancer. Recent data indicate that in addition to cognate ligands, EGFR is activated by UVB irradiation. We used pharmacological and genetic approaches to investigate the function of EGFR in mediating UVB-induced signal transduction in human skin keratinocyte HaCaT cells. Pharmacological inhibition of EGFR tyrosine kinase significantly inhibited UVB-mediated induction of ERK, p38, and JNK MAP kinases, and their effectors, transcription factors c-Fos and c-Jun. Inhibition of UVB activation of EGFR also suppressed activation of AKT-, PKC-, and PKA-dependent signal transduction pathways. B82 mouse L cells devoid of EGFR were used to further investigate EGFR dependence of UVB-induced signal transduction. UVB failed to induce ERK, and JNK activation was reduced 60% in B82 cells compared to B82K+ cells, which express EGFR. In addition, UVB induced both c-Fos and c-Jun proteins in B82K+ cells, whereas neither were induced in B82 cells. Taken together, these data demonstrate that EGFR is required for UVB-mediated induction of multiple signaling pathways that are known to mediate tumor formation in skin.
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PMID:Epidermal growth factor receptor is a critical mediator of ultraviolet B irradiation-induced signal transduction in immortalized human keratinocyte HaCaT cells. 1693 59

The induction of insulin-like growth factor binding protein-1 (IGFBP-1) secretion by rubratoxin B was investigated using human hepatoma cell line HepG2; we also documented the involvement of stress-activated MAP kinases [c-Jun-N-terminal kinases (JNKs) and p38s] in this process. Rubratoxin B dramatically enhanced IGFBP-1 secretion, which peaked at a concentration of 40 microg/ml. The amount of IGFBP-1 mRNA increased with time and plateaued at 6 h. Compared with the amounts of IGFBP-1 secreted, the induction ratios of transcription were much smaller, indicating that IGFBP-1 secretion is regulated chiefly post-transcriptionally. The result of concomitant treatment with rubratoxin B and JNK inhibitor indicated that JNKs do not affect rubratoxin B-induced IGFBP-1 secretion. Alternatively, rubratoxin B-associated induction of IGFBP-1 secretion was marked in the absence of p38 inhibitor but attenuated in its presence. Therefore, p38s appear to stimulate rubratoxin B-induced IGFBP-1 secretion. Treatment with p38 inhibitor slightly increased the amount of rubratoxin B-induced IGFBP-1 mRNA. However this induction ratio was smaller than that of rubratoxin B-induced secretion, suggesting that p38s regulate IGFBP-1 secretion both transcriptionally and post-transcriptionally. In this study, we showed that rubratoxin B induces IGFBP-1 levels in HepG2 cells and p38s contribute to this process.
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PMID:Induced secretion of insulin-like growth factor binding protein-1 (IGFBP-1) in human hepatoma cell HepG2 by rubratoxin B. 1710 17

Acrolein, which is a highly reactive alpha,beta-unsaturated aldehyde generated by lipid peroxidation, can affect cells and tissues and cause various disorders. Increased levels of unsaturated aldehydes play an important role in the pathogenesis of a number of human diseases such as Alzheimer's disease, atherosclerosis and diabetes. Acrolein is a highly ubiquitous toxic environmental pollutant. Because of human exposure, there is a need for investigating the mechanisms involved in acrolein toxicity at the cellular and molecular levels. Acrolein can induce cell death by apoptosis, although the mechanisms are not entirely clear. The present study investigates whether mitogen-activated protein kinases (MAPKs) play a role in activation of apoptosis by acrolein. Our findings show that acrolein-mediated apoptosis is in fact MAPK-dependent in Chinese hamster ovary cells. The MAP family kinases, including ERK and p38 kinase, and the transcription factor c-Jun were all activated by phosphorylation after 1 h exposure to acrolein. Phosphorylation of ERK and p38 kinases and their blockade by an ERK inhibitor, U0126, or a p38 inhibitor, SB203580, respectively, suggested that activation of apoptosis by acrolein is ERK- and p38-dependent. Thus, blockade of ERK and p38 inhibited chromatin condensation, caspase-7 and -9 activation as well as ICAD cleavage induced by acrolein. JNK and AKT kinases seem to be implicated in survival pathways against acrolein insult, since their respective inhibitors, SP600125 and LY294002/Wortmannin switched the mode of cell death from apoptosis to total necrosis. Finally, acrolein induced phosphorylation of the pro-apoptotic factor p53 which is responsible for transcription of pro-apoptotic factors such as Bax and Fas ligand. These results provide new information demonstrating the implication of MAPKs and AKT in acrolein-induced apoptosis, and this information may be useful for understanding the pathogenesis of a number of tissue diseases and environmental toxicity in response to acrolein.
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PMID:P38 and ERK mitogen-activated protein kinases mediate acrolein-induced apoptosis in Chinese hamster ovary cells. 1719 91

Transcription factor AP-1 is a dimer complex composed by DNA-binding proteins of Jun, Fos, and ATF families. AP-1 mediates cell response on growth factors, cytokines, neurotransmitters and other intercellular signaling molecules. AP-1 activity is mediated by G-proteins, adapter proteins, MAP kinases and other elements of cellular signaling systems. AP-1 dependent genes play a pivotal role in regulation of cell proliferation, morphogenesis, apoptosis, and differentiation.
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PMID:[Role of transcription factor AP-1 in integration of cellular signalling systems]. 1720 22

4-Hydroxynonenal (HNE) is one of the most abundant aldehyde components of ox-LDL and it exerts various effects on intracellular and extracellular signaling cascades. In this mini-review, a brief synopsis of HNE-modulated signaling pathways will be presented mainly focused on cell death, including recent studies from our laboratory. The results of a number of studies demonstrate the ability of HNE to induce apoptosis and ROS formation in a dose-dependent manner. Several signaling pathways have been shown to be modulated by HNE, including MAP kinases, PKC isoforms, cell-cycle regulators, receptor tyrosine kinases and caspases. In order to get insight into the mechanisms of apoptotic response by HNE, MAP kinase and caspase activation pathways have been studied in 3T3 fibroblasts; HNE induced early activation of JNK and p38 proteins but down-regulated the basal activity of ERK-1/2. We have shown that HNE-induced release of cytochrome c from mitochondria, caspase-9 and caspase-3 activation. Activation of AP-1 along with increased c-Jun and phospho-c-Jun levels could be inhibited by pretreatment of cells with certain molecules such as resveratrol. Additionally, overexpression of dominant negative c-Jun and JNK1 in 3T3 fibroblasts prevented HNE-induced apoptosis, which indicated a role for JNK-c-Jun/AP-1 pathway. JNK-dependent induction of c-Jun/AP-1 activation data in the literature indicates a critical potential role for JNK in the cellular response against toxic products of lipid peroxidation.
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PMID:Apoptosis signalling by 4-hydroxynonenal: a role for JNK-c-Jun/AP-1 pathway. 1726 5

The mitogen-activated protein kinase (MAPK) phosphatases (MKPs) are a family of dual-specificity protein phosphatases that dephosphorylate both phospho-threonine and phospho-tyrosine residues in MAP kinases, including the c-Jun N-terminal protein kinase (JNK)/stress-activated protein kinase (SAPK), the p38 MAPK, and the extracellular signal-related kinase (ERK). Since phosphorylation is required for the activation of MAP kinases, dephosphorylation by MKPs inhibits MAPK activity, thereby negatively regulating MAPK signaling. It is known that deregulation of MAPK signaling is the most common alteration in human cancers. Recent studies have suggested that MKPs play an important role not only in the development of cancers, but also in the response of cancer cells to chemotherapy. Thus, understanding the roles of MKPs in the development of cancer and their impact on chemotherapy can be exploited for therapeutic benefits for the treatment of human cancer.
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PMID:Role of mitogen-activated protein kinase phosphatases (MKPs) in cancer. 1771 36

Vascular endothelial growth factor (VEGF) is a crucial pro-angiogenic component in pancreatic ductal adenocarcinoma (PDA), and its high expression levels have been correlated with poor prognosis and early postoperative recurrence. We have recently shown that high levels of angiotensin II (AngII) type 1 receptor (AT1R) correlate and colocalize with VEGF in invasive PDA and that AngII induces VEGF expression in PDA cell lines. In this study, we explored the signaling mechanisms involved in the AngII-mediated VEGF induction and correlated AT1R and VEGF expression in noninvasive precursor lesions. An AT1R antagonist significantly (p<0.05) inhibited the AngII-mediated induction of VEGF messenger RNA and protein in all PDA cell lines. AngII-VEGF induction was inhibited by the tyrosine kinase inhibitor genistein, suggesting a mitogen-activated protein kinase signaling mechanism. AngII activated the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), but not p38 or c-Jun NH2-terminal MAP kinases. Inhibition of ERK1/2 activation reduced the AngII-induced VEGF synthesis. Immunohistochemical analysis of precursor lesions showed increased expression of AT1R in most ductal cells undergoing metaplasia. Pancreatic intraepithelial neoplasms showed more intense AT1R staining when compared to intraductal papillary mucinous neoplasms, which showed heterogeneous immunoreactivity. VEGF followed the same distribution pattern of AT1R in both lesions. AT1R expression in the premalignant pancreatic lesions suggests its involvement in tumor progression and angiogenesis. Our mechanistic findings provide the first insight into an AngII-initiated signaling pathway that regulates PDA angiogenesis. An AT1R-mediated VEGF induction suggests the possibility of AT1R blockade as a novel therapeutic strategy to control angiogenesis in PDA.
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PMID:Angiotensin II induces vascular endothelial growth factor in pancreatic cancer cells through an angiotensin II type 1 receptor and ERK1/2 signaling. 1802 17


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