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)

Ultrastructural localization of a specific phosphorylated isomer of myelin basic protein (MBP) has been achieved with a monoclonal antibody specific for human MBP sequence, 89-105, in which Thr98 was phosphorylated. Cryosections of human brain white matter revealed that gold particles were found localized almost exclusively to the major dense line demonstrating that threonine 98 in the sequence Thr-Pro-Arg-Thr-Pro-Pro-Pro, a mitogen-activated protein kinase-specific site, was phosphorylated in vivo. In two cases of multiple sclerosis, the density of gold particles in myelin was reduced by about 30%, in one case by 42%, and by 80% in a fourth case. However, gold labelling was seen in areas of demyelination suggesting that the phosphorylated threonyl peptide was protected from degradation.
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PMID:Identification of a mitogen-activated protein kinase site in human myelin basic protein in situ. 864 64

Tyrosine kinase blockers from the AG 126/AG-556 tyrphostin family are shown to inhibit the lipopolysaccharide (LPS)-induced production of tumor necrosis factor alpha (TNFalpha), nitric oxide (NO), and prostaglandin E2 (PGE2) in primary rat astrocytes cultures. The tyrphostin AG-556 which was previously shown to be effective against sepsis in mice and dogs also show excellent efficacy in inhibiting experimental autoimmune encephalomyelitis (EAE) in mice. AG-556 does not block the activation of JNK/SAPK and of p38/HOG and therefore seems to act at a target down stream to these kinases which is activated in stress or at a target on an obligatory parallel pathway. These findings together with previous results showing inhibition of sepsis in mice and dogs suggest that protein tyrosine kinase (PTK) blockers of the AG-556 family may be considered in the management of human autoimmune disorders such as multiple sclerosis (MS).
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PMID:Suppression of experimental autoimmune encephalomyelitis by tyrphostin AG-556. 987 84

Myelin basic protein (MBP) phosphorylation is a complex regulatory process that modulates the contribution of MBP to the stability of the myelin sheath. Recent research has demonstrated the modulation of MBP phosphorylation by mitogen-activated protein kinase (MAPK) during myelinogenesis and in the demyelinating disease multiple sclerosis. Here we investigated the physiological regulation of MBP phosphorylation by MAPK during neuronal activity in the alveus, the myelinated output fibers of the hippocampus. Using a phosphospecific antibody that recognizes the predominant MAPK phosphorylation site in MBP, Thr95, we found that MBP phosphorylation is regulated by high-frequency stimulation but not low-frequency stimulation of the alveus. This change was blocked by application of tetrodotoxin, indicating that action potential propagation in axons is required. It is interesting that the change in MBP phosphorylation was attenuated by the reactive oxygen species scavengers superoxide dismutase and catalase and the nitric oxide synthase inhibitor N-nitro-L-arginine. Removal of extracellular calcium also blocked the changes in MBP phosphorylation. Thus, we propose that during periods of increased neuronal activity, calcium activates axonal nitric oxide synthase, which generates the intercellular messengers nitric oxide and superoxide and regulates the phosphorylation state of MBP by MAPK.
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PMID:Regulation of myelin basic protein phosphorylation by mitogen-activated protein kinase during increased action potential firing in the hippocampus. 1046 99

Oligodendrocytes are a major target of the purported autoimmune response in multiple sclerosis (MS) lesions, but little is known about the mechanisms underlying their demise. Despite the expression of proapoptotic receptors, these cells are rarely seen to undergo apoptosis in situ. On the other hand, cytotoxic mediators present in MS lesions, such as tumor necrosis factor-alpha, are known to generate survival signals through the activation of the transcription factors NF-kappaB and c-jun. The aim of this study was to investigate in chronic active and silent MS lesions and control white matter the expression of c-jun, its activating molecule, JNK, as well as NF-kappaB complex and its inhibitor, IkappaB. By immunohistochemistry we found negligible reactivity for these molecules in control white matter and silent MS plaques. In active MS lesions, double-label immunohistochemistry with oligodendrocyte markers showed up-regulation of the nuclear staining for both NF-kappaB and JNK on a large proportion of oligodendrocytes located at the edge of active lesions and on microglia/macrophages throughout plaques. Oligodendrocytes showed no reactivity for IkappaB, which was predominantly confined to the cytoplasm of microglia/macrophages. We hypothesize that activation of these transcriptional pathways may be one mechanism accounting for the paucity of oligodendrocyte apoptosis reported in MS.
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PMID:Activation of NF-kappaB and c-jun transcription factors in multiple sclerosis lesions. Implications for oligodendrocyte pathology. 1055 Feb 97

ICAM-1 is a transmembrane glycoprotein of the Ig superfamily involved in cell adhesion. ICAM-1 is aberrantly expressed by astrocytes in CNS pathologies such as multiple sclerosis, experimental allergic encephalomyelitis, and Alzheimer's disease, suggesting a possible role for ICAM-1 in these disorders. ICAM-1 has been shown to be important for leukocyte diapedesis through brain microvessels and subsequent binding to astrocytes. However, other functional roles for ICAM-1 expression on astrocytes have not been well elucidated. Therefore, we investigated the intracellular signals generated upon ICAM-1 engagement on astrocytes. ICAM-1 ligation by a mAb to rat ICAM-1 induced mRNA expression of proinflammatory cytokines such as IL-1alpha, IL-1beta, IL-6, and TNF-alpha. Examination of cytokine protein production revealed that ICAM-1 ligation results in IL-6 secretion by astrocytes, whereas IL-1beta and IL-1alpha protein is expressed intracellularly in astrocytes. The involvement of mitogen-activated protein kinases (MAPKs) in ICAM-1-mediated cytokine expression in astrocytes was tested, as the MAPK extracellular signal-regulated kinase (ERK) was previously shown to be activated upon ICAM-1 engagement. Our results indicate that ERK1/ERK2, as well as p38 MAPK, are activated upon ligation of ICAM-1. Studies using pharmacological inhibitors demonstrate that both p38 MAPK and ERK1/2 are involved in ICAM-1-induced IL-6 expression, whereas only ERK1/2 is important for IL-1alpha and IL-1beta expression. Our data support the role of ICAM-1 on astrocytes as an inflammatory mediator in the CNS and also uncover a novel signal transduction pathway through p38 MAPK upon ICAM-1 ligation.
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PMID:ICAM-1-induced expression of proinflammatory cytokines in astrocytes: involvement of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways. 1103 9

A differential morphological response of mature oligodendrocytes (OL) isolated from human and pig brains to the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) and to the nerve growth factor (NGF) was observed. In both cases, OL regenerate their processes; however, the rate and the extension of the process formation of human OL were behind that of pig OL. Presumably, the advanced age of the human tissue in these experiments might have contributed to this decrease in process formation, an effect that was already observed for rat OL [Yong et al. (1991) J Neurosci Res 29:87-99]. The less effectivity of NGF via TrkA, which was immunocytochemically shown in human OL, and of TPA via the protein kinase C (PKC) pathway, may have its common focus on the mitogen-activated protein kinase (MAPK) cascade. In this context, it was noted that only a few studies on aging of mature OL are available. It is conceivable that age-related changes in the properties of OL could be an important factor for their cellular responsiveness during longer lasting demyelinating diseases such as multiple sclerosis. Hence, this review would like to provide a basis for future investigations on the aging of mature OL. The data presently available suggest a preliminary classification of mature OL into three categories.
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PMID:Differential response of mature TrkA/p75(NTR) expressing human and pig oligodendrocytes: aging, does it matter? 1127 21

Oligodendrocytes play a significant role in the central nervous system, as these cells are responsible for myelinating axons and allowing for the efficient conduction of nerve impulses. Therefore, any understanding we can gain about the functional biology of oligodendrocytes will give us important insights into demyelinating diseases such as multiple sclerosis, where oligodendrocytes and myelin are damaged or destroyed. Currently, much attention has focussed on the role of a family of mitogen-activated protein kinases in OL. This kinase family includes the extracellular signal-regulated protein kinases (ERKs), the stress-activated c-Jun N-terminal kinase (JNK), and the 38 kDa high osmolarity glycerol response kinase (p38). The actions of mitogen-activated protein kinases in oligodendrocytes appear to range from proliferation and cell survival to differentiation and cell death. In the past, studies on oligodendrocytes have been hampered by the difficulties inherent in producing large enough quantities of these cells for experimentation. This problem arises in large part due to the post-mitotic nature of mature oligodendrocytes. Over the years, a cell line known as Central Glia-4 (CG-4) has become a popular oligodendrocyte model due to its potentially unlimited capacity for self-renewal. In this review, we will look at the suitability of the Central Glia-4 cell line as an oligodendrocyte model, specifically in respect to studies on mitogen-activated protein kinase signalling in oligodendrocytes.
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PMID:Mitogen-activated protein kinase signalling in oligodendrocytes: a comparison of primary cultures and CG-4. 1137 2

CD40 is a protein on microglia that is up-regulated with interferon (IFN)-gamma and is engaged by CD40L, found on CD4+ T cells, B cells, and monocytes. These interactions may be important in central nervous system inflammatory diseases. Microglia have been shown to be a source of chemokines, whose expression plays a key role in central nervous system pathologies. We examined the expression of CD40 on microglia in human immunodeficiency virus (HIV) encephalitic brain, and the effects of CD40-CD40L interactions on the expression of chemokines by cultured microglia. We found significantly increased numbers of CD40-positive microglia in HIV-infected brain tissue. Treatment of cultured microglia with IFN-gamma and CD40L increased expression of several chemokines. IFN-gamma- and CD40L-induced MCP-1 protein was mediated by activation of the ERK1/2 MAPK pathway, and Western blot analysis demonstrated phosphorylation of ERK1/2 upon stimulation of microglia. In contrast, IFN-gamma- and CD40L-induced IP-10 protein production was mediated by the p38 MAPK pathway. Our data suggest a mechanism whereby CD40L+ cells can induce microglia to secrete chemokines, amplifying inflammatory processes seen in HIV encephalitis and multiple sclerosis, and implicate CD40-CD40L interactions as a target for interventional strategies.
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PMID:CD40-CD40L interactions induce chemokine expression by human microglia: implications for human immunodeficiency virus encephalitis and multiple sclerosis. 1183 76

Interleukin (IL)-10 is synthesized in the central nervous system (CNS) and acts to limit clinical symptoms of stroke, multiple sclerosis, Alzheimer's disease, meningitis, and the behavioral changes that occur during bacterial infections. Expression of IL-10 is elevated during the course of most major diseases in the CNS and promotes survival of neurons and all glial cells in the brain by blocking the effects of proapoptotic cytokines and by promoting expression of cell survival signals. Stimulation of IL-10 receptors regulates numerous life- or death-signaling pathways--including Jak1/Stat3, PI 3-kinase, MAPK, SOCS, and NF-kappaB--ultimately promoting cell survival by inhibiting both ligand- and mitochondrial-induced apoptotic pathways. IL-10 also limits inflammation in the brain; it does so by three major pathways: (1) reducing synthesis of proinflammatory cytokines, (2) suppressing cytokine receptor expression, and (3) inhibiting receptor activation. Finally, IL-10 induces anergy in brain-infiltrating T cells by inhibiting cell signaling through the costimulatory CD28-CD80/86 pathway. The multiple functions of IL-10 in the brain will create new and intriguing vistas that will promote a better understanding of neurodegenerative diseases. These discoveries could lead to development of innovative approaches for the use of antiinflammatory cytokines in major debilitating diseases of the CNS.
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PMID:Interleukin-10 in the brain. 1194 58

Microglia, the resident brain macrophages, are the principal cells involved in the regulation of inflammatory and antimicrobial responses in the CNS. Interferon-beta (IFNbeta) is an antiviral cytokine induced by viral infection or following non-specific inflammatory challenges of the CNS. Because of the well-known anti-inflammatory properties of IFNbeta, it is also used to treat multiple sclerosis, an inflammatory CNS disease. Despite the importance of IFNbeta signaling in CNS cells, little has been studied, particularly in microglia. In this report, we investigated the molecular mechanisms underlying IFNbeta-induced beta-chemokine expression in primary human fetal microglia. Multiple signaling cascades are activated in microglia by IFNbeta, including nuclear factor-kappaB (NF-kappaB), activator protein-1 (AP-1) and Jak/Stat. IFNbeta induced IkappaBalpha degradation and NF-kappaB (p65:p50) DNA binding. Inhibition of NF-kappaB by either adenoviral transduction of a super repressor IkappaBalpha, or an antioxidant inhibitor of NF-kappaB reduced expression of the beta-chemokines, regulated upon activation, normal T-cell expressed and secreted (RANTES) and macrophage inflammatory protein (MIP)-1beta. IFNbeta also induced phosphorylation of extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase, and the MAP kinase kinase 1 (MEK1) inhibitor PD98059 dose-dependently inhibited beta-chemokine mRNA and protein expression. PD98059 did not inhibit NF-kappaB binding, demonstrating that ERK was not responsible for NF-kappaB activation. Two downstream targets of ERK were identified in microglia: AP-1 and Stat1. IFNbeta induced AP-1 nuclear binding activity in microglia and this was suppressed by PD98059. Additionally, IFNbeta induced Stat1 phosphorylation at both tyrosine 701 (Y701) and serine 727 (S727) residues. S727 phosphorylation of Stat1, which is known to be required for maximal transcriptional activation, was inhibited by PD98059. Our results demonstrating multiple signaling cascades initiated by IFNbeta in primary human microglia are novel and have implications for inflammatory and infectious diseases of the CNS.
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PMID:Interferon-beta activates multiple signaling cascades in primary human microglia. 1206 83


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