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)

Recent studies suggest that the aryl hydrocarbon receptor (AhR) modulates susceptibilities to some pro-apoptotic agents. AhR-containing murine hepatoma 1c1c7 cultures underwent apoptosis following exposure to tumor necrosis factor-alpha (TNFalpha) + cycloheximide (CHX). In contrast, Tao cells, an AhR-deficient variant of the 1c1c7 line, were refractory to this treatment. AhR sense/antisense transfection studies demonstrated that AhR contents influenced susceptibility to the pro-apoptotic effects of TNFalpha + CHX. 1c1c7 cells and all variants expressed comparable amounts of TNF receptor-1 and TRADD. However, no cell line expressed FADD, and consequently pro-caspase-8 was not activated. AhR content did not influence JNK and NF-kappaB activation. However, Bid and pro-caspase-9, -3, and -12 processing occurred only in AhR-containing cells. Analyses of cathepsin B and D activities in digitonin-permeabilized cultures and the monitoring of cathepsin B/D co-localization with Lamp-1 indicated that TNFalpha + CHX disrupted late endosomes/lysosomes in only AhR-containing cells. Stabilization of acidic organelles with 3-O-methylsphingomyelin inhibited TNFalpha + CHX-induced apoptosis. The cathepsin D inhibitor pepstatin A suppressed in vitro cleavage of Bid by 1c1c7 lysosomal extracts. It also delayed the induction of apoptosis and partially prevented Bid cleavage and the activation of pro-caspases-3/7 in cultures treated with TNFalpha + CHX. Similar suppressive effects occurred in cultures transfected with murine Bid antisense oligonucleotides. These studies showed that in cells where pro-caspase-8 is not activated, TNFalpha + CHX can initiate apoptosis through lysosomal disruption. Released proteases such as cathepsin D trigger the apoptotic program by activating Bid. Furthermore, in the absence of exogenous ligand, the AhR modulates lysosomal disruption/permeability.
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PMID:Aryl hydrocarbon receptor modulation of tumor necrosis factor-alpha-induced apoptosis and lysosomal disruption in a hepatoma model that is caspase-8-independent. 1644 72

The yeast Sln1p sensor kinase is best known as an osmosensor involved in the regulation of the hyperosmolarity glycerol mitogen-activated protein kinase cascade. Down-regulation of Sln1 kinase activity occurs under hypertonic conditions and leads to phosphorylation of the Hog1p mitogen-activated protein kinase and increased osmotic stress-response gene expression. Conditions leading to kinase up-regulation include osmotic imbalance caused by glycerol retention in the glycerol channel mutant, fps1 (Tao, W., Deschenes, R. J., and Fassler, J. S. (1999) J. Biol. Chem. 274, 360-367). The hypothesis that Sln1p kinase activity is responsive to turgor was first suggested by the increased Sln1p kinase activity in mutants lacking Fps1p in which glycerol accumulation leads to water uptake. Also consistent with the turgor hypothesis is the observation that reduced turgor caused by treatment of cells with nystatin, a drug that increases membrane permeability and causes cell shrinkage, reduced Sln1p kinase activity (Tao, W., Deschenes, R. J., and Fassler, J. S. (1999) J. Biol. Chem. 274, 360-367; Reiser, V., Raitt, D. C., and Saito, H. (2003) J. Cell Biol. 161, 1035-1040). The turgor hypothesis is revisited here in the context of the identification and characterization of the cell wall gene, CCW12, as a determinant of Sln1p activity. Results of this analysis suggest that the activity of the plasma membrane localized Sln1p is affected by the presence or absence of specific outer cell wall proteins and that this effect is independent of turgor.
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PMID:Modulation of yeast Sln1 kinase activity by the CCW12 cell wall protein. 1804 66

Protease-activated receptor-2 (PAR2) is a 7-transmembrane G-protein-coupled tethered ligand receptor that is expressed by pancreatic acinar and ductal cells. It can be physiologically activated by trypsin. Previously reported studies (Namkung, W., Han, W., Luo, X., Muallem, S., Cho, K. H., Kim, K. H., and Lee, M. G. (2004) Gastroenterology 126, 1844-1859; Sharma, A., Tao, X., Gopal, A., Ligon, B., Andrade-Gordon, P., Steer, M. L., and Perides, G. (2005) Am. J. Physiol. 288, G388-G395) have shown that PAR2 activation exerts a protective effect on the experimental model of pancreatitis induced by supramaximal secretagogue (caerulein) stimulation. We now show that PAR2 exerts a worsening effect on a different model of experimental pancreatitis, i.e. one induced by retrograde pancreatic ductal infusion of bile salts. In vitro studies using freshly prepared pancreatic acini show that genetic deletion of PAR2 reduces bile salt-induced pathological calcium transients, acinar cell injury, and activation of c-Jun N-terminal kinase, whereas genetic deletion of PAR2 has the opposite or no effect on these pancreatitis-related events when they are elicited, in vitro, by caerulein stimulation. Studies employing a combination of trypsin inhibition and activation of PAR2 with the activating peptide SLIGRL show that all these differences indeed depend on the activation of PAR2. These studies are the first to report that a single perturbation can have model-specific and opposite effects on pancreatitis, and they underscore the importance of performing mechanistic pancreatitis studies using two dissimilar models of the disease to detect idiosyncratic, model-specific events. We suggest PAR2 activation exerts a worsening effect on the severity of clinical pancreatitis and that interventions interfering with PAR2 activation may be of benefit in the treatment of patients with severe pancreatitis.
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PMID:Protease-activated receptor-2 exerts contrasting model-specific effects on acute experimental pancreatitis. 1851 23

This article has been retracted at the request of: Editor-in-Chief and Authors 'Cross-talk of alpha tocopherol-associated protein and JNK controls the oxidative stress-induced apoptosis in prostate cancer cells' by Baoyi Zhu, Xiaojuan Li, Yuying Zhang, Chunwei Ye, Yu Wang, Songwang Cai, Huaiqiu Huang, Yi Cai, Shuyuan Yeh, Zhenhua Huang, Ruihan Chen, Yiran Tao and Xingqiao Wen The above article, published online on 28 November 2012 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors, the journal Editor-in-Chief, Prof. Peter Lichter, and Wiley Periodicals, Inc. The Retraction has been agreed due to errors that were detected in Fig. 6b. Some images were duplicated and erroneously presented as unique. Although the authors firmly stand by the major conclusion of this paper, they believe the most responsible course of action is to retract it. Reference Zhu, B., Li, X., Zhang, Y., Ye, C., Wang, Y., Cai, S., Huang, H., Cai, Y., Yeh, S., Huang, Z., Chen, R., Tao, Y. and Wen, X. (2013), Cross-talk of alpha tocopherol-associated protein and JNK controls the oxidative stress-induced apoptosis in prostate cancer cells. Int. J. Cancer, 132: 2270-2282. doi: 10.1002/ijc.27927.
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PMID:Retraction. 2312 85

Cisplatin (CP) is one of the most effective chemotherapeutics in the treatment of human cancers. However, the beneficial effects of CP are limited by the toxic effects, especially nephrotoxicity. Fluorofenidone (AKFPD) is a promising multifunctional antifibrosis pyridinone drug discovered by our group. But there is no evidence of its protective effects against acute kidney injury (AKI). Therefore, we investigated the protective effects of AKFPD on CP-induced AKI in vivo and in vitro. Compared with the model group, treatment with AKFPD effectively ameliorated kidney damages. In order to elucidate the mechanisms, we discovered that AKFPD treatment notably alleviated generation of reactive oxygen species, reduced the phosphorylation levels of MAPKs (ERK1 and 2, JNKs, and p38), suppressed inflammatory response, inhibited apoptosis, and abated the expression of CP transporters (organic cation transporter 2 and copper transport protein 1) compared with the model group. Moreover, because renal ischemia reperfusion injury (IRI)-induced AKI and LPS-induced AKI are the major models representative of renal transplantation-correlated AKI and sepsis-related AKI, which are also the main causes of AKI, we have also proved the effectiveness of AKFPD on these models. In conclusion, these findings suggest that AKFPD is a potent drug for CP-, IRI-, and LPS-caused AKI and elucidate the underlying mechanism.-Jiang, Y., Quan, J., Chen, Y., Liao, X., Dai, Q., Lu, R., Yu, Y., Hu, G., Li, Q., Meng, J., Xie, Y., Peng, Z., Tao, L. Fluorofenidone protects against acute kidney injury.
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PMID:Fluorofenidone protects against acute kidney injury. 3166 38