Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pyrrolidine dithiocarbamate (PDTC) is known to induce cell death by the stimulation of intracellular zinc transport and subsequent modulation of nuclear factor-kappaB (NF-kappaB) activity. Zinc is a signaling messenger that is released by neuronal activity at many central excitatory synapses. Excessive synaptic release of zinc followed by entry into vulnerable neurons contributes to severe neuronal cell death. In the present study, we explored how PDTC modulates intracellular signal transduction pathways, leading to neuronal cell death. The exposure of immortalized embryonic hippocampal cells (H19-7) to PDTC within the range of 1-100 microM caused cell death in a dose-dependent manner. During the cell death, NF-kappaB activity increased in response to PDTC, and this activity corresponded well with the increase of intracellular free zinc levels, implying that the activation of NF-kappaB transmits the cell death signals of PDTC. Furthermore, PDTC caused the activation of IkappaB kinase (IKK), casein kinase 2 (CK2), phosphatidylinositol 3-kinase (PI-3K), and Akt, as well as mitogen-activated protein kinases (MAPKs), such as extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), but not p38 kinase. The blockade of PI-3K, JNK, and CK2 pathways resulted in a remarkable suppression of PDTC-induced cell death and also the activation of IKK, which subsequently led to a decrease of IkappaB phosphorylation. Although the overexpression of dominant-negative SEK in a transient manner did not inhibit the activation of Akt by PDTC, the transfection of kinase-inactive Akt mutants did cause a remarkable blockade of JNK activation, implying that Akt is present upstream of JNK in the PDTC-signaling pathways. Moreover, whereas selective CK2 inhibitors suppressed PDTC-induced JNK activation, the inhibition of JNK did not affect CK2 activity, suggesting that CK2 is directly related to the regulation of cell viability by PDTC and that the CK2-JNK pathway could be a downstream target of PDTC. Taken together, our results suggest that PDTC-mediated accumulation of intracellular zinc ions may affect cell viability by modulating several intracellular signaling pathways in neuronal hippocampal progenitor cells.
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PMID:Pyrrolidine dithiocarbamate-induced neuronal cell death is mediated by Akt, casein kinase 2, c-Jun N-terminal kinase, and IkappaB kinase in embryonic hippocampal progenitor cells. 1258 27

Positive pressure ventilation with large tidal volumes has been shown to cause release of cytokines, including interleukin (IL)-8. The mechanisms regulating lung stretch-induced cytokine production are unclear. We hypothesized that stretch-induced IL-8 production is dependent on the activation of the mitogen-activated protein kinases, c-Jun NH2-terminal kinases (JNK), p38, and/or extracellular signal-regulated kinase (ERK) 1/2. We exposed A549 cells, a type II-like alveolar epithelial cell line, to cyclic stretch at 20 cycles/min for 5 min-2 h. Cyclic stretch induced IL-8 protein production, IL-8 mRNA expression, and JNK activation, but only transient activation of p38 and ERK1/2. Inhibition of stretch-induced JNK activation by adenovirus-mediated gene transfer of stress-activated protein kinase (SEK-1), a dominant-negative mutant of SEK-1, the immediate upstream activator of the JNKs, and pharmacological JNK inhibitor II SP-600125 blocked IL-8 mRNA expression and attenuated IL-8 production. Inhibition of p38 and ERK1/2 did not affect stretch-induced IL-8 production. Stretch-induced activation NF-kappaB and activator protein (AP)-1 was blocked by NF-kappaB inhibitor and JNK inhibitor, respectively. An NF-IL-6 site was not essential for cyclic stretch-induced IL-8 promoter activity. Stretch also induced NF-kappaB-inducing kinase (NIK) activation, and inhibition of NF-kappaB attenuated IL-8 mRNA expression and IL-8 production. We conclude that stretch-induced transcriptional regulation of IL-8 mRNA and IL-8 production was via activation of AP-1 and NF-kappaB and was dependent on JNK and NIK activation, respectively.
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PMID:Stretch-induced IL-8 depends on c-Jun NH2-terminal and nuclear factor-kappaB-inducing kinases. 1271 52

Docosahexaenoic acid (DHA) causes apoptosis of various cancer cells, but the mechanism of DHA-induced cell death is still unclear. We hypothesized that the early signaling of apoptosis may be important in causing cell death as well as the production of free radical metabolites. DHA caused time- and dose-dependent cell death in human HepG2 hepatoma cells transduced with CYP2E1 (E47) but not in C34 (without CYP2E1), suggesting an important role of CYP2E1 in the DHA-mediated damage. DHA increased the c-Jun N-terminal protein kinase (JNK) activity until 8 h without activating other mitogen-activated protein kinases. The contents of proapoptotic Bad and FasL at 4 h and cytochrome c and caspase 3 activity at 8 h were increased and accompanied by the JNK activation in a successive manner. In contrast, Bax and Bcl-2 were not changed. Levels of lipid peroxides (LPOs) were elevated three- and fivefold at 8 and 24 h, respectively, in DHA-induced E47 cells. However, pretreatment with chlormethiazole (CMZ), a specific inhibitor of CYP2E1, significantly reduced the levels of LPO, CYP2E1, JNK activity and the rate of cell death. In addition, pretreatment with quercetin (one as a JNK inhibitor and one as an antioxidant) significantly reduced the cell death rate and JNK and SEK-1 activities. Our results indicated that DHA-mediated apoptosis in E47 cells was induced through the activation of the JNK-related cell death pathway, which may be involved in the production of LPO or reactive oxygen species during the CYP2E1 catalytic cycle, followed by mitochondrial injury and apoptosis.
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PMID:Docosahexaenoic acid induces apoptosis in CYP2E1-containing HepG2 cells by activating the c-Jun N-terminal protein kinase related mitochondrial damage. 1696 49

Phosphorylation is the most common and important mechanism of acute and reversible regulation of protein function. Studies of mammalian cells metabolically labeled with [(32)P]orthophosphate suggest that as many as one-third of all cellular proteins are covalently modified by protein phosphorylation. Protein phosphorylation has an important role in essentially all aspects of cell biology. Most polypeptide growth factors (platelet-derived growth factor and epidermal growth factor are among the best studied) and cytokines (e.g., interleukin 2, colony stimulating factor 1, and gamma-interferon) stimulate phosphorylation upon binding to their receptors. Induced phosphorylation in turn activates cytoplasmic protein kinases, such as Raf, the activators of the mitogen-activated protein (MAP) kinases SEK and MEK, the MAP kinases ERK, JNK, and p38, the Janus/JAK kinases, the p21 activated kinases (PAKs), and the phosphatidylinsoitil 3'-kinase-activated kinase, protein kinase B/Akt. Additionally, in all nucleated organisms, cell cycle progression is regulated at both the G1/S and the G2/M transitions by cyclin-dependent protein kinases. These kinases regulate the G1/S transition by the phosphorylation of cell cycle regulators such as Rb protein and the G2/M transition through the phosphorylation of nuclear lamins and histones.
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PMID:Overview of protein phosphorylation. 1822 24


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