Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Silica has been known to be a factor inducing acute injury and chronic pulmonary fibrosis. Silica has also been listed as a human carcinogen in 1996 by International Agency for Research on Cancer (IARC). However, the molecular mechanisms involved its pathologic effects are not well understood. In these studies, we found that exposure of human embryonic lung fibroblasts (HELF) to crystalline silica could cause increases in activation of extracellular signal-regulated kinases (ERKs), p38K, and c-Jun NH2-terminal amino kinases (JNKs), and HELF transformation. Interestingly, silica-induced transformation of HELF (S-HELF) led to increases in activated levels of ERKs and p46 of JNKs, and decrease in p38K activation, and no effect on activation of p54 of JNKs, as compared with those in parental HELF. Further studies showed that there are differential effects of ERKs, JNKs and p38K, as well as their downstream transcription factor AP-1, in regulation of expression of cyclin D1 and CDK4 and cell cycle alternations induced by silica. Cyclin D1 and CDK4 were increased in S-HELF as compared with those in HELF. Inhibition of ERKs activation by AG126, JNK by SP600125, and AP-1 by curcumin could reduced the induction of cyclin D1 and CDK4. There is no significant difference for cell cycle distribution between groups. These results demonstrate that ERKs and JNKs, but not p38K is responsible for induction of cyclin D1 and CDK4 in S-HELF, suggesting that overexpression of cyclin D1 and CDK4 caused by silica is mediated by ERK, JNK/AP-1signaling pathway.
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PMID:Overexpression of cyclin D1-CDK4 in silica-induced transformed cells is due to activation of ERKs, JNKs/AP-1 pathway. 1612 82

Mechanical loading is thought to be an important stimulus regulating muscle mass. However, the responsiveness of a muscle atrophied by a period of mechanical unloading to a subsequently imposed mechanical challenge is not well understood. This study examined the phosphorylation of the mechanically sensitive p54 c-jun NH(2)-terminal kinase (JNK) signaling protein in atrophied rat soleus muscle in response to a mechanical challenge in situ (isometric contractions; 100 Hz, 150 ms, once every 1 s for 5 min). Rats underwent either 7 or 14 days of hindlimb suspension (HLS) following which phosphorylation of JNK was measured biochemically. Immunofluorescence analysis revealed that phosphorylated JNK was localized in myonuclei. Baseline JNK phosphorylation measured in non-stimulated soleus muscles of 7- and 14-day HLS groups was 3.0- and 2.8-fold, respectively, the baseline phosphorylation measured in muscle of weight-bearing control animals (CTL). Following a mechanical challenge, JNK phosphorylation in stimulated CTL and 7-day HLS groups was significantly increased by 3.2- and 1.8-fold at the non-stimulated baseline levels, respectively. In stimulated muscle of 14-day HLS, JNK phosphorylation levels did not significantly differ from the baseline levels suggesting that the ability to elicit a mechanically induced phosphorylation of the JNK signaling protein gradually decreases with unweighting and is attenuated after 14-day HLS. Changes in the responsiveness of mechanically sensitive intracellular signaling pathways in atrophic muscle may contribute to the functional impairment experienced by muscle in the absence of weight bearing for prolonged periods.
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PMID:Sensitivity of rat soleus muscle to a mechanical stimulus is decreased following hindlimb unweighting. 1618 43

Mitogen-activated protein kinases (MAPK) play a pivotal role in ischemia reperfusion injuries of heart and liver, but the activation pattern of MAPKs in the early phase of different size liver isografts remains unclear. The experiment is designed to investigate the activation pattern and role of MAPKs in isografts of the rat with different size liver transplantation. The animal models of different size graft liver transplantation (whole graft, 50% size, or 30% size, respectively) were established and the sham operation group served as a control. The recipients were sacrificed at 0.5-, 2-, 6-, and 24-hour time points after transplantation to harvest the graft specimens and blood samples. The serum aspartate amino transferase (AST), alanine amino transferase (ALT) and tumor necrosis factor-alpha (TNF-alpha) levels, and histological findings were evaluated. The expressions of the total and phosphorylated p46/p54 JNKs, p38 MAPK, and p42/p44 ERKs were detected by Western blot. The serum ALT and AST levels increased significantly at the 0.5-hour time point and maintained high with the peak levels at the 6-hour time point after liver transplantation. The different sizes of liver isografts did not change the expressions of total p46/p54JNKs, p38MAPK, and p42/p44 ERKs. While the expressions of phosphorylated p46/p54JNKs, p38 MAPK, and p42/p44 ERKs were either negative or mildly up-regulated in the sham operation group, they were significantly activated in the transplanted liver at the 0.5-hour time point, especially in the 30% size liver transplantation group. In conclusion, the activation of three MAPKs in liver isografts correlates with graft size and the JNK and p38 MAPK are responsible for the graft injury while the ERK signal pathway maybe participate in the regulation of cell growth and differentiation after small-for-size liver transplantation.
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PMID:Activation pattern of mitogen-activated protein kinases in early phase of different size liver isografts in rats. 1631 91

Flavonoids including luteolin, apigenin, and fisetin are inhibitors of IL-4 synthesis and CD40 ligand expression by basophils. This study was done to search for compounds with greater inhibitory activity of IL-4 expression and to clarify the molecular mechanisms through which flavonoids inhibit their expression. Of the 37 flavonoids and related compounds examined, ayanin, luteolin, and apigenin were the strongest inhibitors of IL-4 production by purified basophils in response to anti-IgE antibody plus IL-3. Luteolin did not suppress Syk or Lyn phosphorylation in basophils, nor did suppress p54/46 SAPK/JNK, p38 MAPK, and p44/42 MAPK activation by a basophilic cell line, KU812 cells, stimulated with A23187 and PMA. However, luteolin did inhibit phosphorylation of c-Jun and DNA binding activity of AP-1 in nuclear lysates from stimulated KU812 cells. These results provide a fundamental structure of flavonoids for IL-4 inhibition and demonstrate a novel action of flavonoids that suppresses the activation of AP-1.
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PMID:Luteolin, a flavonoid, inhibits AP-1 activation by basophils. 1634 31

Ras proteins are signal transducers for many cellular responses. However, it is not well established whether Ras-signaling also contributes to apoptosis. We have constructed H-RasR12-transformed Rat1 fibroblasts using tetracycline operator/repressor (TetO/TetR)-based conditional vectors. Rat1/TetO-RasR12 (Rat1-Ras) cells produced high levels of H-RasR12 protein and exhibited oncogenic transformation. Treatment of Rat1-Ras cells with 0.1% serum triggered massive apoptosis. Rat1-Ras cells expressed increased basal activities of extracellular response kinase (ERK) and p46/p54 stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK). Interestingly, Ras-dependent apoptosis correlated with further persistent activation of both p46 and p54 SAPK/JNK and concurrent inhibition of ERK. Differential modulation of SAPK/JNK and ERK was not detected in tetracycline-treated cells that did not commit apoptosis. Furthermore, two Bcl-x related proteins of 15 kDa and 18 kDa were highly induced in apoptotic Rat1-Ras cells. Our results establish a direct role for Ras in apoptosis, and suggest a functional relationship between H-Ras, SAPK/JNK, ERK and Bcl-x in regulating apoptosis.
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PMID:Ras-dependent apoptosis correlates with persistent activation of stress-activated protein kinases and induction of isoform(s) of Bcl-x. 1646 87

The sphingoid base sphinganine induces apoptosis in HT-29 human colon cancer cells more potently than other bioactive sphingolipid metabolites sphingosine and C2-ceramide tested in our previous study. The objective of this study was to investigate the effect of sphinganine, at a concentration that induces apoptosis, on the mitogen activated protein kinases (MAPKs) including ERK1/ERK2, JNK2/JNK1, and p38 MAPK and AKT (protein kinase B), which regulate cell proliferation and apoptosis. HT-29 cells were cultured with sphinganine at 35 microM and the protein expression and phosphorylation status of ERK1/ERK2 (p44/p42), JNK2/JNK1 (p54/p46), p38 MAPK, and AKT were determined using Western blot analysis. Sphinganine clearly increased the active phosphorylated forms of JNK2/JNK1 and p38 MAPK after 15, 30, and 60 min treatment, with minimal effects on activation of ERK1/ERK2. Sphinganine weakly inhibited the phosphorylation of AKT at ser473 after 30 and 60 min. Sphinganine had little or no effect on the protein expression level of any of the kinases. The findings are consistent with a mechanism by which sphinganine induces apoptosis in HT-29 cells via early and strong activation of JNK and p38 MAPK and weak inhibition of AKT activation.
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PMID:Sphinganine causes early activation of JNK and p38 MAPK and inhibition of AKT activation in HT-29 human colon cancer cells. 1647 87

Previous studies have shown that the cardioprotective effect of ischemic preconditioning (IPC) can be mimicked pharmacologically with clinically relevant agents, including nitric oxide (NO) donors. However, whether pharmacological preconditioning shares the same molecular mechanism with IPC is not fully elucidated. The present study aimed to determine the activation of mitogen-activated protein kinases (MAPKs) (ERK1/2, p38 MAPK and p46/p54 JNKs) during ischemia and at reperfusion in nitroglycerin-induced preconditioning as compared to IPC and to correlate this with the conferred cardioprotection in anesthetized rabbits. Sixty minutes of intravenous administration of nitroglycerin was capable of inducing both early and late phase preconditioning in anesthetized rabbits, as it was expressed by the reduction of infarct size. Despite the cardioprotective effect conferred by both ischemic and nitroglycerin-induced preconditioning, there was a differential phosphorylation of MAPKs between the studied groups. p38 MAPK was activated early in ischemia in both ischemic and the early nitroglycerin-induced preconditioning while JNKs were markedly increased only after IPC. Furthermore, in these groups, ERK1/2 were activated during reperfusion. A different profile was observed in the late preconditioning induced by nitroglycerin with increased p38 MAPK and ERK1/2 phosphorylation during late ischemia. No activation of JNKs was observed at any time point in this group. It seems that activation of individual MAPK subfamilies depends on the nature of preconditioning stimulus.
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PMID:Differential activation of mitogen-activated protein kinases in ischemic and nitroglycerin-induced preconditioning. 1661 56

Mitogen-activated protein kinase (MAPK) cascades transmit and amplify signals involved in cell proliferation as well as in cell death. In this study, the potential derangement of MAPK pathways has been evaluated in human squamous cell carcinomas (SCC) of the larynx. The expression and activity of the MAPK p38, ERK1/2p44/p42 and JNK/SAPKp46/p54 have been investigated by immunoblot analysis of tissue homogenates in 27 samples of primary laryngeal cancer and in 27 paired non-neoplastic laryngeal mucosa. On the same tissues, the activation of MAPK JNK/SAPKp46/p54 was also analyzed by an ELISA assay. The results obtained showed that both total and phosphorylated levels of JNK/SAPKp46/p54 and p38 were not different between tumor and normal samples. Conversely, while total protein levels for both ERK1p44 and ERK2p42 were not statistically different between tumor and normal samples, the analysis of the level of the activated forms of ERK1/2 showed a statistically significant decreased phosphorylation of both isoforms in the tumor samples compared to the control tissues. The rate of reduction was similar for both isoforms. Immunohistochemical analysis of all the activated MAPK (p38, JNK/SAPKp46/p54 and ERK1/2p44/p42) in both laryngeal SCC and normal mucosa demonstrated no difference of cellular localization. Activated ERK1/2p44/p42 and activated p38 demonstrated a nucleo-cytoplasmic distribution whereas activated JNK/SAPKp46/p54 were localized into the cytoplasmic membrane. The decreased activity of ERK1/2p44/42 in laryngeal SCC might reflect alterations in tumor suppressing activity or might derive from the interplay among various transduction pathways.
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PMID:Selective reduction of extracellular signal-regulated protein kinase (ERK) phosphorylation in squamous cell carcinoma of the larynx. 1686 46

The effect of fractionated doses of Co(60) gamma-irradiation (2 Gy per fraction over 5 days), as is delivered in cancer radiotherapy, was compared with acute doses of 10 and 2 Gy, in a serially transplanted mouse fibrosarcoma grown in Swiss mice. The aspects that were studied included the three major mitogen-activated protein (MAP) kinases, namely p44 MAP kinase, p38 MAP kinase, and stress-activated protein (SAP) kinase, which are known to be involved in determining the cell fate following exposure to ionizing radiation. The response of dual specificity phosphatase PAC1 which is involved in the dephosphorylation of MAP kinases was also looked at. There were significant differences in the response to different dose regimens for all the factors studied. Fractionated irradiation elicited an adaptive response with a sustained activation over 7 days of prosurvival p44 MAP kinase which was balanced by the increased activation of proapoptotic p54 SAP kinase up to 1 day post-irradiation, whereas, phosphorylated p38 MAP kinase showed a decrease at most time points. PAC1 was induced following fractionated irradiation and may be acting as a feed back regulator of p44 MAP kinase. The activation of SAP kinase after fractionated irradiation may be a stress response, whereas, constitutively activated p44 MAP kinase may play an important role in the induction of radioresistance during fractionated radiotherapy of cancer and may serve as a promising target for specific inhibitors to enhance the efficacy of radiotherapy.
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PMID:Fractionated and acute irradiation induced signaling in a murine tumor. 1722 87

Androgens, like estrogens, have been linked to neuroprotective effects in the brain and to the improvement of cognitive function. Part of this effect may be due to the action of androgens on the innate immune response. We have examined the action of dihydrotestosterone (DHT) and testosterone on immune activation in primary cultures of microglia, the central nervous system macrophage. Our data indicate that DHT acts as an antiinflammatory agent and depresses both nitric oxide and TNFalpha production in a dose-dependent fashion. However, testosterone treatment of microglia and peritoneal macrophages increased supernatant nitrite levels, indicative of a proinflammatory effect. Because the apolipoprotein E (APOE) genotype also dramatically impacts macrophage function and has been linked to neurodegenerative disease, we compared the effects of APOE genotype on androgen-mediated regulation of inflammation using targeted replacement mice expressing only the human APOE3 or human APOE4 gene. Our data show that the antiinflammatory activity of DHT is significantly reduced in APOE4 targeted replacement mice compared to APOE3 mice. The effect was not due to an APOE isoform-specific change in androgen receptor mRNA and protein expression. Rather, innate immune signaling pathways regulated by androgens are altered in the APOE4 microglia. Compared to APOE3 microglia, DHT treatment did not reduce the phosphorylation of p38 MAPK or p54/p56 Janus kinase in APOE4 mice. Thus, our data suggest that DHT modulation of kinase activity is altered in microglia from mice expressing an APOE4 genotype and may impact androgen treatment therapies in individuals with an APOE4 genotype.
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PMID:Androgen-mediated immune function is altered by the apolipoprotein E gene. 1739 8


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