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)

Eicosapentaenoic acid (EPA; 20:5, n-3) can restrain tumor growth and metastasis in vivo; however, the mechanism of its antitumor effect is still not fully understood. Angiogenesis is a crucial process for tumor growth and metastasis and inhibition of tumor angiogenesis can suppress tumor growth and metastasis in vivo. Vascular endothelial growth factor (VEGF) is an important angiogenic factor. In this study, we investigated the mechanisms of the inhibitory effect of EPA on VEGF-induced proliferation of bovine carotid artery endothelial (BAE) cells. BAE cells, treated with 0-5 microg/ml EPA for 48 h, displayed a dose-dependent suppression to VEGF (0.2 nM)-induced proliferation. Similar inhibitory effect was not found in BAE cells treated with arachidonic acid (AA; 20:4, n-6), or docasahexaenoic acid (DHA; 22:5, n-3). In contrast to its effect on VEGF-induced proliferation, EPA had no inhibition to basic fibroblast growth factor (bFGF, 0.2 nM)-induced proliferation in BAE cells. Both VEGF and bFGF activated mitogen-activated protein (MAP) kinase in BAE cells; however, EPA selectively inhibited VEGF-induced, but not bFGF-induced activation of MAP kinase. Flk-1 expression was inhibited dose-dependently in EPA-treated cells, whereas Flt-1 expression was increased in EPA treated cells. This in vitro inhibitory effect by EPA on Flk-1 receptor expression provides indirect evidence that one of the mechanisms of EPA for antitumor action in vivo maybe related to its antiangiogenic action.
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PMID:Eicosapentaenoic acid attenuates vascular endothelial growth factor-induced proliferation via inhibiting Flk-1 receptor expression in bovine carotid artery endothelial cells. 964 21

This study was conducted on human Jurkat T cell lines to elucidate the role of EPA and DHA, n-3 PUFA, in the modulation of two mitogen-activated protein (MAP) kinases, that is, extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2). The n-3 PUFA alone failed to induce phosphorylation of ERK1/ERK2. We stimulated the MAP kinase pathway with anti-CD3 antibodies and phorbol 12-myristate 13-acetate (PMA), which act upstream of the MAP kinase (MAPK)/ERK kinase (MEK) as U0126, an MEK inhibitor, abolished the actions of these two agents on MAP kinase activation. EPA and DHA diminished the PMA- and anti-CD3-induced phosphorylation of ERK1/ERK2 in Jurkat T cells. In the present study, PMA acts mainly via protein kinase C (PKC) whereas anti-CD3 antibodies act via PKC-dependent and -independent mechanisms. Furthermore, DHA and EPA inhibited PMA-stimulated PKC enzyme activity. EPA and DHA also significantly curtailed PMA- and ionomycin-stimulated T cell blastogenesis. Together these results suggest that EPA and DHA modulate ERK1/ERK2 activation upstream of MEK via PKC-dependent and -independent pathways and that these actions may be implicated in n-3 PUFA-induced immunosuppression.
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PMID:Eicosapentaenoic acid and docosahexaenoic acid modulate MAP kinase (ERK1/ERK2) signaling in human T cells. 1173 74

The trichothecene mycotoxin deoxynivalenol (DON) induces IgA hyperelevation and mesangial IgA deposition in mice that mimics the early stages of human IgA nephropathy (IgAN). Among potential mediators of this disease, interleukin-6 (IL-6) is likely to play a particularly critical role in IgA elevation and disease exacerbation. Based on previous findings that dietary fish oil (FO) suppresses DON-induced IgAN, we hypothesized that FO inhibits the induction of IL-6 expression by this mycotoxin in vivo and in vitro. Mice were fed modified AIN 93G diet amended with 7% corn oil (CO) or with 1% corn oil plus 6% menhaden fish oil (FO) for up to 8 weeks and then exposed acutely to DON by oral gavage. DON-induced plasma IL-6 and splenic mRNA elevation in FO-fed mice were significantly suppressed after 8 weeks when compared to the CO-fed group. The effects of FO on phosphorylation of mitogen-activated protein kinases (MAPKs), critical upstream transducers of IL-6 up-regulation, were also assessed. DON-induced phosphorylation of extracellular signal regulated protein kinases 1 and 2 (ERK1/2) and c-Jun N-terminal kinases 1 and 2 (JNK1/2) was significantly suppressed in spleens of mice fed with FO, whereas p38 was not. Splenic COX-2 mRNA expression, which has been previously shown to enhance DON-induced IL-6, was also significantly decreased by FO, whereas plasma levels of the COX-2 metabolite, prostaglandin E2, were not affected. To confirm in vivo findings, the effects of pretreatment with the two primary n-3 PUFAs in FO, eicosapentaenoic acid (20:5[n-3]; EPA) and docosahexaenoic acid, (22:6[n-3]; DHA), on DON-induced IL-6 expression were assessed in LPS-treated RAW 264.7 macrophage cells. Consistent with the in vivo findings, both EPA and DHA significantly suppressed IL-6 superinduction by DON, as well as impaired DON-induced ERK1/2 and JNK1/2 phosphorylation. In contrast, the n-6 PUFA arachidonic acid (20:4[n-3]) had markedly less effects on these MAPKs. Taken together, the capacity of FO and its component n-3 PUFAs to suppress IL-6 expression as well as ERK 1/2 and JNK 1/2 activation might explain, in part, the reported suppressive effects of these lipids on DON-induced IgA nephropathy.
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PMID:Deoxynivalenol-induced mitogen-activated protein kinase phosphorylation and IL-6 expression in mice suppressed by fish oil. 1469 Jul 64