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)

Cardiotrophin-1 (CT-1) is a member of the IL-6 family of cytokines which was originally discovered as a factor which can induce hypertrophy of cardiac myocytes both in vitro and in vivo. Subsequently, CT-1 has been shown to have a wide variety of different effects on cardiac and non cardiac cells including the ability to stimulate the survival of both cardiac and neuronal cells. Interestingly, whilst activation of the p42/p44 MAP kinase pathway is necessary for the survival promoting effects of CT-1 in cardiac cells, it is not required for its hypertrophic effect which is likely to involve activation of the Jak/STAT-3 pathway. CT-1 may therefore be of use as a novel cardio-protective agent, particularly if its hypertrophic effect can be specifically inhibited.
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PMID:Cardiotrophin-1 (CT-1): a novel hypertrophic and cardioprotective agent. 1058 28

Cardiotrophin-1 (CT-1) originally was discovered as a factor that can induce hypertrophy of cardiac myocytes, both in vitro and in vivo. Subsequently, CT-1 has been shown to have a wide variety of different effects on cardiac and noncardiac, cells including the ability to stimulate the survival of both cardiac and neuronal cells. Like other members of the interleukin-6 family of cytokines, CT-1 stimulates both the p42/p44 mitogen-activated protein kinase pathway and the Janus-activated kinase/signal transducers and activators of transcription pathway. Interestingly, whilst activation of the p42/p44 mitogen-activated protein kinase pathway is necessary for the survival-promoting effects of CT-1 in cardiac cells, it is not required for its hypertrophic effect, which is likely to involve activation of the Janus-activated kinase/signal transducer and activator of transcription-3 pathway. CT-1, therefore, may be of use as a novel cardioprotective agent, particularly if its hypertrophic effect can be specifically inhibited.
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PMID:Cardiotrophin-1: a novel cytokine and its effects in the heart and other tissues. 1067 12

Interleukin (IL)-6-related cytokines share gp130 as the signal-transducing protein. Cardiac myocytes produce various kinds of cytokines including IL-6 and cardiotrophin-1. Activation of gp130 transduces hypertrophic and cytoprotective signals in cardiac myocytes via JAK/STAT, MAP kinase and PI-3 kinase pathways. Besides various well-established mechanisms by which cardiac growth and myocardial remodeling are regulated, gp130 signalling may be a newly discovered mechanism that regulates these events in association with cytoprotective effect in myocardial diseases.
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PMID:Cytokines and their receptors in cardiovascular diseases--role of gp130 signalling pathway in cardiac myocyte growth and maintenance. 1071 60

Interleukin (IL)-6-related cytokines share gp130 as the signal-transducing protein. Cardiac myocytes produce various kinds of cytokines including IL-6 and cardiotrophin-1. Activation of gp130 transduces hypertrophic and cytoprotective signals in cardiac myocyte via JAK/STAT, MAP kinase and PI-3 kinase pathways. Besides various well-established mechanisms by which myocardial hypertrophy and remodeling are regulated, a gp130 signaling may be a newly discovered mechanism that regulates these events in association with cytoprotective effect in cardiomyopathy. In addition, the activation of gp130 dependent signaling pathway in cardiac myocytes might play a pivotal role in the prevention of heart failure.
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PMID:[Role of cytokine signaling in cardiomyopathy]. 1088 19

Myocardial reperfusion injury represents an important therapeutic target. The ability of several peptide growth factors, including transforming growth factor-beta1, insulin, insulin-like growth factor-1, cardiotrophin-1 and fibroblast growth factors, to modify reperfusion injury has been examined in recent studies. The protective effects of these agents may be related to the inhibition of apoptosis, especially during reperfusion, probably through p42/p44 MAP kinase and PI3-kinase/Akt signaling. Growth factor signaling may therefore represent a novel approach for the development of pharmacological strategies that attenuate reperfusion injury in the heart.
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PMID:Reperfusion injury revisited: is there a role for growth factor signaling in limiting lethal reperfusion injury? 1109 33

Cardiotrophin-1 (CT-1) is an Interleukin-6 family cytokine with known hypertrophic and protective effects in cardiac cells. CT-1 and the corticotrophin releasing hormone-like hormone urocortin protect cardiac myocytes by the same p42/44 mitogen activated protein kinase (p42/44 MAPK) dependent pathway. We investigated whether urocortin is also hypertrophic in cardiac myocytes and whether it shares a common pathway with CT-1 for this effect. Moreover, we also investigated, for the first time whether CT-1 and urocortin can induce hypertrophy in cultured adult as opposed to neonatal cardiac cells. Urocortin and CT-1 caused hypertrophy (as measured by an increase in cell area and enhanced protein: DNA ratio) in both adult and neonatal rat cultured cardiac myocytes. The hypertrophic effect of CT-1 was dependent on the signal transducer and activator of transcription 3 (STAT3) pathway but the hypertrophic effect of urocortin was independent of this pathway. In contrast, inhibition of the protective p42/p44 MAPK pathway has no effect on the hypertrophic effect of CT-1 or urocortin. Additionally, inhibition of the STAT3 pathway has no effect on the protective effect of CT-1 or urocortin. These results identify urocortin as a novel hypertrophic and protective agent whose hypertrophic effect is mediated by a distinct pathway to that activated by CT-1, although the two factors mediate protection via the same pathway.
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PMID:Cardiotrophin-1 and urocortin cause protection by the same pathway and hypertrophy via distinct pathways in cardiac myocytes. 1202 5

Gene therapy for neurodegenerative diseases may utilize the expression of neurotrophic factors because of their potential to promote survival and regeneration of injured neuronal cells. Increasing numbers of these factors are being considered for gene transfer, but their specificity and efficacy in neuroprotection are greatly variable. The major aims of this study were to carry out gene transfer of various neurotrophic factors and investigate their mechanisms of action as well as their protective effects on the viability of rat pheochromocytoma (PC12) cells. We used glutamate, S-nitroso-N-acetyl-DL-penicillamine (SNAP), and staurosporine to induce excitatory damage, oxidative stress, and apoptosis, respectively, because these mechanisms are thought to participate in various disease processes leading to degeneration of cells. We utilized adenovirus vectors for efficient gene transfer of trophic factors (glial-cell derived neurotrophic factor [GDNF] and cardiotrophin-1 [CT-1]) or calbindin-D28k. We found that GDNF and CT-1 gene transfers were equally effective in saving PC12 cells from injury, but calbindin expression did not show any beneficial effects. GDNF gene transfer was much more efficient in protecting PC12 cells from damage than direct GDNF administration. The protection by GDNF expression against staurosporine was mediated through both phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase kinase (MAPK kinase; MEK) pathways, but only the MEK pathway was involved in the protection against SNAP. In contrast, the protective effect of GDNF against glutamate toxicity was independent of these RET-dependent signal transduction pathways.
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PMID:Gene transfer of glial cell-derived neurotrophic factor and cardiotrophin-1 protects PC12 cells from injury: involvement of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase kinase pathways. 1221 Aug 28

Oncostatin M (OSM) is a member of the IL-6/LIF (or gp130) cytokine family, and its potential role in inflammation is supported by a number of activities identified in vitro. In this study, we investigate the action of murine OSM on expression of the CC chemokine eotaxin by fibroblasts in vitro and on mouse lung tissue in vivo. Recombinant murine OSM stimulated eotaxin protein production and mRNA levels in the NIH 3T3 fibroblast cell line. IL-6 could regulate a small induction of eotaxin in NIH 3T3 cells, but other IL-6/LIF cytokines (LIF, cardiotrophin-1 (CT-1)) had no effect. Cell signaling studies showed that murine OSM, LIF, IL-6, and CT-1 stimulated the tyrosine phosphorylation of STAT-3, suggesting STAT-3 activation is not sufficient for eotaxin induction in NIH 3T3 cells. OSM induced ERK-1,2 and p38 mitogen-activated protein kinase phosphorylation in NIH 3T3 cells, and inhibitors of ERK (PD98059) or p38 (SB203580) could partially reduce OSM-induced eotaxin production, suggesting partial dependence on mitogen-activated protein kinase signaling. OSM (but not LIF, IL-6, or CT-1) also induced eotaxin release by mouse lung fibroblast cultures derived from C57BL/6 mice. Overexpression of murine OSM in lungs of C57BL/6 mice using an adenovirus vector encoding murine OSM resulted in a vigorous inflammatory response by day 7 after intranasal administration, including marked extracellular matrix accumulation and eosinophil infiltration. Elevated levels of eotaxin mRNA in whole lung were detected at days 4 and 5. These data strongly support a role of OSM in lung inflammatory responses that involve eosinophil infiltration.
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PMID:Oncostatin M regulates eotaxin expression in fibroblasts and eosinophilic inflammation in C57BL/6 mice. 1249 42

The IL (interleukin)-6-type cytokines IL-6, IL-11, LIF (leukaemia inhibitory factor), OSM (oncostatin M), ciliary neurotrophic factor, cardiotrophin-1 and cardiotrophin-like cytokine are an important family of mediators involved in the regulation of the acute-phase response to injury and infection. Besides their functions in inflammation and the immune response, these cytokines play also a crucial role in haematopoiesis, liver and neuronal regeneration, embryonal development and fertility. Dysregulation of IL-6-type cytokine signalling contributes to the onset and maintenance of several diseases, such as rheumatoid arthritis, inflammatory bowel disease, osteoporosis, multiple sclerosis and various types of cancer (e.g. multiple myeloma and prostate cancer). IL-6-type cytokines exert their action via the signal transducers gp (glycoprotein) 130, LIF receptor and OSM receptor leading to the activation of the JAK/STAT (Janus kinase/signal transducer and activator of transcription) and MAPK (mitogen-activated protein kinase) cascades. This review focuses on recent progress in the understanding of the molecular mechanisms of IL-6-type cytokine signal transduction. Emphasis is put on the termination and modulation of the JAK/STAT signalling pathway mediated by tyrosine phosphatases, the SOCS (suppressor of cytokine signalling) feedback inhibitors and PIAS (protein inhibitor of activated STAT) proteins. Also the cross-talk between the JAK/STAT pathway with other signalling cascades is discussed.
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PMID:Principles of interleukin (IL)-6-type cytokine signalling and its regulation. 1277 95

The corticotrophin-releasing hormone-related factor, urocortin (Ucn) and the interleukin (IL)-6 family cytokine cardiotrophin-1 (CT-1) are both cardioprotective agents able to protect the heart from ischemic damage. In both cases the protective effect involves activation of the p42/p44 MAPK and PI-3 kinase/Akt pathways, but the protective effect of Ucn requires de novo protein synthesis whereas that of CT-1 does not. In this study, we show that Ucn induces enhanced expression of CT-1 at both the mRNA and protein levels. This effect is mediated by activation of the CT-1 gene promoter and requires the transcription factor C/EBPbeta/NF-IL6. Hence, a specific cardioprotective factor can induce enhanced expression of another cardioprotective factor belonging to an unrelated protein family.
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PMID:The cardioprotective agent urocortin induces expression of CT-1. 1455 90


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