Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The stress activated protein kinase pathway culminates in c-Jun phosphorylation mediated by the Jun Kinases (JNKs). The role of the JNK pathway in sympathetic neuronal death is unclear in that apoptosis is not inhibited by a dominant negative protein of one JNK kinase, SEK1, but is inhibited by CEP-1347, a compound known to inhibit this overall pathway but not JNKs per se. To evaluate directly the apoptotic role of the JNK isoform that is selectively expressed in neurons, JNK3, we isolated sympathetic neurons from JNK3-deficient mice and quantified nerve growth factor (NGF) deprivation-induced neuronal death, oxidative stress, c-Jun phosphorylation, and c-jun induction. Here, we report that oxidative stress in neurons from JNK3-deficient mice is normal after NGF deprivation. In contrast, NGF-deprivation-induced increases in the levels of phosphorylated c-Jun, c-jun, and apoptosis are each inhibited in JNK3-deficient mice. Overall, these results indicate that JNK3 plays a critical role in activation of c-Jun and apoptosis in a classic model of cell-autonomous programmed neuron death.
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PMID:JNK3 contributes to c-Jun activation and apoptosis but not oxidative stress in nerve growth factor-deprived sympathetic neurons. 1146 65

Acetaminophen (AAP), a widely used analgesic drug, can damage various organs when taken in large doses. In this study, we investigate whether AAP causes cell damage by altering the early signaling pathways associated with cell death and survival. AAP caused time- and concentration-dependent apoptosis and DNA fragmentation of C6 glioma cells used as a model. AAP activated c-Jun N-terminal protein kinase (JNK) by 5.3-fold within 15 min. The elevated JNK activity persisted for up to 4 h before it returned to the basal level at 8 h. In contrast, activities of other mitogen-activated protein (MAP) kinases and the level of Akt phosphorylation in the cell survival pathway remained unchanged throughout the treatment. Wortmannin, an inhibitor of phosphatidylinositol-3 kinase, or SB203580, an inhibitor of p38 MAP kinase, did not reduce AAP-induced toxicity, indicating that these enzymes do not play a major role in cell toxicity. AAP-induced apoptosis was preceded by the sequential elevation of the pro-apoptotic Bax protein, cytochrome c release, and caspase-3 activity. Treatment with caspase inhibitor benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethyl ketone (Z-DEVD-FMK) significantly reduced AAP-induced caspase-3 activation and cytotoxicity. Transfection of cDNA for the dominant-negative mutant JNK-KR or stress-activated protein kinase kinase-1 Lys-->Arg mutant (SEK1-KR), an immediate upstream kinase of JNK, significantly reduced AAP-induced JNK activation and cell death rate. The noncytotoxic analog of AAP, 3-hydroxyacetanilide, neither increased JNK activity nor caused apoptosis. Pretreatment with YH439, an inhibitor of CYP2E1 gene transcription, markedly reduced CYP2E1 mRNA, protein content, and activity, as well as the rate of AAP-induced JNK activation and cell death. These data indicate that AAP can cause cell damage by activating the JNK-related cell death pathway, providing a new mechanism for AAP-induced cytotoxicity.
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PMID:Acetaminophen induces apoptosis of C6 glioma cells by activating the c-Jun NH(2)-terminal protein kinase-related cell death pathway. 1156 48

The protein serine-threonine kinase Akt mediates cell survival signaling initiated by various growth-promoting factors such as insulin. Here we report that SEK1 is a target of Akt in intact cells. Insulin inhibited the anisomycin-induced stimulation of both endogenous SEK1 and its substrate c-Jun N-terminal kinase (JNK), but not that of the upstream kinase MEKK1, in 293T cells. The inhibitory action of insulin on SEK1 or JNK1 activation was prevented by the phosphatidylinositol 3-kinase inhibitor LY294002. Expression of a constitutively active form of Akt also inhibited both SEK1 and JNK1 activation, but not that of MEKK1, in transfected 293T cells. Co-immunoprecipitation analysis revealed that endogenous Akt physically interacted with endogenous SEK1 in cells and that this interaction was promoted by insulin. In vitro and in vivo (32)P labeling indicated that Akt phosphorylated SEK1 on serine 78. The SEK1 mutant SEK1(S78A) was resistant to Akt-induced inhibition. Finally, activated Akt inhibited SEK1-mediated apoptosis, and this effect of Akt was prevented by overexpression of SEK(S78A). Taken together, these results suggest that Akt suppresses stress-activated signaling by targeting SEK1.
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PMID:Akt (protein kinase B) negatively regulates SEK1 by means of protein phosphorylation. 1170 64

293 kidney embryonic cells feature very low levels of the anti-apoptotic protein PED. In these cells, expression of PED to levels comparable with those occurring in normal adult cells inhibits apoptosis induced by growth factor deprivation and by exposure to H(2)O(2) or anisomycin. In PED-expressing 293 cells (293(PED)), inhibition of apoptosis upon growth factor deprivation was paralleled by decreased phosphorylation of JNK1/2. In 293(PED) cells, decreased apoptosis induced by anisomycin and H(2)O(2) was also accompanied by block of JNK1/2 and p38 phosphorylations, respectively. Impaired activity of these stress kinases by PED correlated with inhibition of stress-induced Cdc-42, MKK4, and MKK6 activation. At variance with JNK1/2 and p38, PED expression increased basal and growth factor-stimulated Ras-Raf-1 co-precipitation and MAPK phosphorylation and activity. Treatment of 293(PED) cells with the MEK inhibitor PD98059 blocked ERK1/2 phosphorylations with no effect on inhibition of JNK1/2 and p38 activities. Complete rescue of JNK and p38 functions in 293(PED) cells by overexpressing JNK1 or p38, respectively, enabled only partial recovery of apoptotic response to growth factor deprivation and anisomycin. However, simultaneous rescue of JNK and p38 activities accompanied by block of ERK1/2 fully restored these responses. Thus, PED controls activity of the ERK, JNK, and p38 subfamilies of MAPKs. PED anti-apoptotic function in the 293 cells requires PED simultaneous activation of ERK1/2 and inhibition of the JNK/p38 signaling systems by PED.
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PMID:Multiple members of the mitogen-activated protein kinase family are necessary for PED/PEA-15 anti-apoptotic function. 1179 Jul 85

Mitogen-activated protein (MAP) kinase pathways are three-kinase modules that mediate diverse cellular processes and have been highly conserved among eukaryotes. By using a functional complementation screen in yeast, we have identified a human MAP kinase kinase kinase (MAPKKK) that shares homology with members of the mixed lineage kinase (MLK) family and therefore was called MRK (MLK-related kinase). We report the structure of the MRK gene, from which are generated two splice forms of MRK, MRK-alpha and MRK-beta, encoding for proteins of 800 and 456 amino acids, respectively. By using a combination of solid phase protein kinase assays, transient transfections in cells, and analysis of endogenous proteins in stably transfected Madin-Darby canine kidney cells, we found that MRK-beta preferentially activates ERK6/p38gamma via MKK3/MKK6 and JNK through MKK4/MKK7. We also show that expression of wild type MRK increases the cell population in the G(2)/M phase of the cell cycle, whereas dominant negative MRK attenuates the G(2) arrest caused by gamma-radiation. In addition, exposure of cells to gamma-radiation induces MRK activity. These data suggest that MRK may mediate gamma-radiation signaling leading to cell cycle arrest and that MRK activity is necessary for the cell cycle checkpoint regulation in cells.
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PMID:MRK, a mixed lineage kinase-related molecule that plays a role in gamma-radiation-induced cell cycle arrest. 1183 44

Cellular N-Ras provides a steady-state antiapoptotic signal, at least partially through the regulation of phosphorylated Akt and Bad levels. Fibroblasts lacking c-N-Ras expression are highly sensitive to the induction of apoptosis by a variety of agents. Reduction of pBad and pAkt levels using a phosphatidylinositol 3-kinase inhibitor was not sufficient to sensitize the control cell population to the high level of apoptosis observed in the N-Ras knockout cell lines, suggesting that c-N-Ras provides at least one other antiapoptotic signal. Stimulation of the control cells with apoptotic agents results in a transient increase in Jun N-terminal protein kinase (JNK)/p38 activity that decreased to baseline levels during the time course of the experiments. In all cases, however, sustained JNK/p38 activity was observed in cells lacking c-N-Ras expression. This correlated with sustained levels of phosphorylated MKK4 and MKK3/6, upstream activators of JNK and p38, respectively. Mimicking the sustained activation of JNK in the control cells did result in increasing their sensitivity to apoptotic agents, suggesting that prolonged JNK activity is a proapoptotic event. We also examined the potential downstream c-N-Ras targets that might be involved in regulating the duration of the JNK/p38 signal. Only the RalGDS 37G-N-Ras protein protected the N-Ras knockout cells from apoptosis and restored transient rather than sustained JNK activation. These data suggest that cellular N-Ras provides an antiapoptotic signal through at least two distinct mechanisms, one which regulates steady-state pBad and pAkt levels and one which regulates the duration of JNK/p38 activity following an apoptotic challenge.
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PMID:Cellular N-Ras promotes cell survival by downregulation of Jun N-terminal protein kinase and p38. 1183 24

The vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating polypeptide (PACAP), two immunomodulatory neuropeptides, act as anti-inflammatory factors for activated microglia, by inhibiting the production of proinflammatory factors. In the present study the effects of VIP/PACAP on the MEKK1/MEK4/JNK transduction pathway and on the subsequent changes in Jun family members, a transduction pathway clearly involved in the activation of microglia cells were examined. VIP/PACAP inhibit MEKK1 activity and the subsequent phosphorylations of MEK4, JNK, and c-Jun, which result in a decrease in the AP-1 binding and a marked change in the composition of AP-1 complexes from c-Jun/c-Fos to JunB/c-Fos. Furthermore, VIP stimulates JunB production in LPS-stimulated microglia. Both inhibition of the MEKK1/MEK4/JNK pathway, leading to a reduction in phosphorylated c-Jun, and the stimulation of JunB are mediated through the specific VPAC1 receptor and cAMP/PKA pathway. The VIP/PACAP interference with the stress-induced SAPK/JNK pathway in activated microglia may represent a significant element in the regulation of inflammatory response in the CNS by endogenous neuropeptides.
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PMID:Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit the MEKK1/MEK4/JNK signaling pathway in endotoxin-activated microglia. 1205 37

Previously, we established HEp2 cell lines which express the US3 protein kinase of herpes simplex virus type 2 upon induction with IPTG. Using these cells, we examined whether expression of US3 is sufficient to protect cells from apoptotic cell death induced by sorbitol. Cells expressing US3 showed significantly reduced nuclear fragmentation in the degree that DNA fragmentation and caspase-3 activation were suppressed. It is known that stressors such as osmotic shock and UV irradiation induce the activation of the JNK (c-Jun N-terminal kinase), which can lead to apoptotic cell death. Expression of US3 resulted in the suppression of sorbitol-induced phosphorylation of JNK and MKK4/SEK1, suggesting that the suppression of apoptotic cell death was due to the attenuation of JNK activity.
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PMID:Herpes simplex virus type 2 US3 blocks apoptosis induced by sorbitol treatment. 1206 30

To investigate the role of intracellular mitogen activated protein kinase (MAPKs, ERK, JNK and p38) signal pathways in IL-1beta -stimulated alpha-smooth muscle actin (alpha-SMA) expression in rat mesangial cells (rMC), alpha-SMA-promoter gene was transfected into rMC by electro-perforation method and the promoter activity was assayed after IL-1beta (10 ng/ml) stimulation. Protein expression of alpha-SMA was assayed by Western blot. The results were compared between the groups stimulated by IL-1beta with or without PD98059 and SB203580, which are thought to block ERK and p38 pathway, respectively. Dominant-negative-JNKK plasmid was co-transfected in rMC to block JNK pathway. The spatial distribution of alpha-SMA and microfilament-like structure was observed by a confocal laser scanning microscope or an electric microscope. After 6 or 24 h of incubation with IL-1beta, rMC underwent a phenotypic change, which was represented by up-regulation of alpha-SMA promoter activity and protein expression. An increase in alpha-SMA and microfilament-like structure was found around the cell nucleus. Block of JNK and/or p38 pathway greatly inhibited IL-1beta -induced alpha-SMA expression, and the block of p38 pathway also suppressed the basal level of alpha-SMA expression. In contrast, ERK pathway had no influence on the process. It is, therefore, concluded that IL-1beta -stimulated expression of alpha-SMA is due to its protein synthesis and cytoskeleton re-organization in activated rMC. Intracellular signal regulation of alpha-SMA expression seems to be mediated mainly by JNK/p38 pathways, but ERK appears to have no effect on the process.
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PMID:[IL-1beta stimulates alpha-smooth muscle actin expression through JNK/p38 signal pathway in cultured rat mesangial cells]. 1207 73

To identify phosphoproteins that might play a role in naringin-sensitive hepatocellular cytoskeletal disruption and apoptosis induced by algal toxins, hepatocyte extracts were separated by gel electrophoresis and immunostained with a phosphothreonine-directed antibody. Use of dilute (5%) polyacrylamide gels containing 6 m urea allowed the resolution of one very large (approximately 500-kDa) okadaic acid- and naringin-sensitive phosphoprotein, identified by tryptic fingerprinting, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and immunostaining as the cytolinker protein, plectin. The naringin-sensitive phosphorylation induced by okadaic acid and microcystin-LR probably reflected inhibition of a type 2A protein phosphatase, whereas the naringin-resistant phosphorylation induced by calyculin A, tautomycin, and cantharidin probably involved a type 1 phosphatase. Okadaic acid caused a collapse of the plectin-immunostaining bile canalicular sheaths and the general cytoskeletal plectin network into numerous medium-sized plectin aggregates. Inhibitors of protein kinase C, cAMP-dependent protein kinase, or Ca(2+)/calmodulin-dependent kinase II had moderate or no protective effects on plectin network disruption, whereas naringin offered 86% protection. Okadaic acid induced a naringin-sensitive phosphorylation of AMP-activated protein kinase (AMPK), the stress-activated protein kinases SEK1 and JNK, and S6 kinase. The AMPK-activating kinase (AMPKK) is likely to be the target of inhibition by naringin, the other kinases serving as downstream components of an AMPKK-initiated signaling pathway.
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PMID:Naringin-sensitive phosphorylation of plectin, a cytoskeletal cross-linking protein, in isolated rat hepatocytes. 1209 91


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