Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Methotrexate (MTX) has been widely used for the treatment of inflammatory diseases and rheumatoid arthritis (RA), as well as a variety of tumors. However, MTX-induced toxicity is a serious and unpredictable side effect of this therapy and an important clinical problem. We used microarray analysis to examine MTX-induced gene expression in a human lung epithelial cell line (BEAS-2B) and identified 10 differentially expressed genes related to the p38 mitogen-activated protein kinase (MAPK) pathway, including IL-1beta, MKK6, and MAPKAPK2. Differential gene expression was confirmed via real-time RT-PCR. To determine the functional significance of MTX-induced p38 MAPK activation, we used a p38 MAPK inhibitor (SB203580) to block the p38 MAPK cascade. We also used protein array technology to investigate the modulated expression of pro- and anti-inflammatory cytokines in BEAS-2B cells. MTX activated IL-1beta expression and induced the phosphorylation of various proteins in the p38 MAPK cascade, including TAK1, MKK3/MKK6, p38 MAPK, MAPKAPK2, and HSP27. Finally, HSP27 activation may increase IL-8 secretion, resulting in a pulmonary inflammatory response such as pneumonitis. Although IL-1beta and IL-8 expression increased, the expression of IL-4, IL-6, IL-12, TNF-alpha, MIP-1alpha, and MIP-1beta decreased in a dose-dependent manner. These results suggest that the modulation of cytokine expression may play an important role in MTX-induced pulmonary toxicity.
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PMID:Inflammation in methotrexate-induced pulmonary toxicity occurs via the p38 MAPK pathway. 1910 Mar 7

Development of p38alpha inhibitors for rheumatoid arthritis has been hindered by toxicity and limited efficacy. Therefore, we evaluated whether MKK6, an upstream kinase that regulates multiple p38 isoforms, might be an alternative therapeutic target in inflammatory arthritis. Wild-type (WT), MKK6(-/-), and MKK3(-/-) mice were administered K/BxN serum to induce arthritis. Articular expression of activated kinases and cytokines was determined by Western blot, qPCR, ELISA, and multiplex analysis. Immunoprecipitation and confocal microscopy experiments were performed to determine the subcellular location of MKK6, P-p38, and MAPKAPK2 (MK2). Arthritis scores were significantly lower in MKK6(-/-) mice compared with WT mice. Joint destruction and osteoclast differentiation were lower in MKK6(-/-), as were articular IL-6 and matrix metalloproteinase-3 expression. Phospho-p38 levels were modestly decreased in the joints of arthritic MKK6(-/-) mice compared with WT but were significantly higher than MKK3(-/-) mice. P-MK2 was low in MKK6(-/-) and MKK3(-/-) mice. Uncoupled p38 and MK2 activation was also observed in cultured, MKK6(-/-) FLS and confirmed using kinase assays. Immunoprecipitation assays and confocal microscopy showed that P-p38 and MK2 colocalized in activated WT but not MKK6(-/-) FLS. Distinct patterns of cytokine production were observed in MKK6(-/-) and MKK3(-/-) cells. MKK6 deficiency suppresses inflammatory arthritis and joint destruction, suggesting it might be a therapeutic target for inflammation. Although MKK3 and MKK6 activate the p38 pathway, they regulate distinct subsets of proinflammatory cytokines. MKK6 appears mainly to facilitate p38 and MK2 colocalization in the nucleus rather than to phosphorylate p38.
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PMID:Role of MAPK kinase 6 in arthritis: distinct mechanism of action in inflammation and cytokine expression. 1956 Oct 96

There is increasing evidence that p38 MAPK, which is classified as a stress-activated kinase, also participates in cell cycle regulation, functioning as a suppressor of cell proliferation and tumorigenesis. We conducted a study of p38 MAPK phosphorylation during liver regeneration in mice to determine whether p38 MAPK activation or inactivation may correlate with events that lead to DNA replication after partial hepatectomy (PH), and whether p38 MAPK activation may be required for hepatocyte DNA replication in vivo and in culture. We report that active p38 (Pi-p38 MAPK) is present in normal liver, is rapidly inactivated starting 30 min after PH, and is re-activated by 12h. Although levels of Pi-MKK 3/6, the upstream kinases that activate p38 MAPK increase after PH, the expression of the dual protein phosphatase 1 is also elevated, and may be responsible for Pi-p38 MAPK dephosphorylation after PH. Inactivation and re-activation of p38 MAPK inversely correlates with the stimulation of protein synthesis and translation pathways, as indicated by activation of p70S6 kinase, increases in the phosphorylation of initiation factor elF-4E and translational repressor, 4E-BP. The activity of a p38 MAPK downstream substrate, MAPKAPK2 (MK2), did not reflect the changing levels of Pi-p38 MAPK during liver regeneration. Pi-p38 MAPK may be involved in TNF-stimulated DNA replication of murine hepatocytes in culture, but is not necessary for hepatocyte DNA replication after PH. Our results suggest that p38 MAPK inactivation plays a permissible role in DNA replication during liver regeneration and is consistent with a role for p38 MAPK in the maintenance of hepatocyte cell cycle arrest in adult liver.
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PMID:Inactivation of p38 MAPK during liver regeneration. 2070 92

To investigate whether and on which pathway dietary calcium influence the obesity induced by high-fat diet, thirty male Kunming mice were fed in six groups for 4 weeks and mouse preadipocytes were divided into eight groups for different treatment. Body weight gain was measured each week. Calcium in serum and tissues, intracellular free Ca(2+) concentration ([Ca(2+)]i), blood fat and intracellular lipid content were also measured. The expression of Lipid metabolism-related genes were measured by q RT-PCR. Compared with control group, body weight gain (P < 0.05) and fat pad weight (P < 0.01) in Low calcium group decreased. Triglycerides (TG) and total Cholesterol (TC) level decreased (P < 0.01), while HDL-Cholesterol (HDL) level increased (P < 0.01). And calcium supply increased calcium content in blood serum and tissues. In tissues, adipogenesis and vitamin D receptor (VDR) genes expression decreased but lipoclasis genes expression increased. These anti-obesity effects were more obvious when supplying with 2.8% calcium, but the effects were reduced while supplying Nifedipine at the same time. The results in preadipocytes indicated that calcium-treated can reduce intracellular lipid content, along with adipogenesis and lipoclasis genes expression decrease, promoted the expression levels of p38 MAPK pathway upstream gene MKK6 (P < 0.01) and downstream gene MAPKAPK2 (P < 0.01). Treated with SB203580 could increase adipogenesis genes expression, decrease lipoclasis genes expression and ([Ca(2+)]i) (P < 0.01). These results implied that dietary calcium had remarkable effect on anti-obesity effect and p38 MAPK pathway potentially participated in calcium-mediated lipid accumulation and lipolysis in mouse preadipocytes.
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PMID:Calcium ameliorates obesity induced by high-fat diet and its potential correlation with p38 MAPK pathway. 2163 89


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