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)

Previous studies from other laboratories suggest that linoleic acid and its metabolites, hydroperoxyoctadecadienoic acids, play an important role in modulating the growth of some cells. A correlation has been demonstrated between hydroperoxyoctadecadienoic acids and conditions characterized by abnormal cell growth such as atherosclerosis and psoriasis. To determine if linoleic acid and its metabolites modulate cell growth in atherosclerosis, we measured DNA synthesis, protooncogene mRNA expression, and mitogen-activated protein kinase (MAPK) activation in vascular smooth muscle cells (VSMC). Linoleic acid induces DNA synthesis, c-fos, c-jun, and c-myc mRNA expression and MAPK activation in VSMC. Furthermore, nordihydroguaiaretic acid, a potent inhibitor of the lipoxygenase system, significantly reduced the growth-response effects of linoleic acid in VSMC, suggesting that conversion of linoleic acid to hydroperoxyoctadecadienoic acids (HPODEs) is required for these effects. HPODEs also caused significant induction of DNA synthesis, protooncogene mRNA expression, and MAPK activation in growth-arrested VSMC, suggesting that linoleic acid and its metabolic products, HPODEs, are potential mitogens in VSMC, and that conditions such as oxidative stress and lipid peroxidation which provoke the production of these substances may alter VSMC growth.
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PMID:Linoleic acid and its metabolites, hydroperoxyoctadecadienoic acids, stimulate c-Fos, c-Jun, and c-Myc mRNA expression, mitogen-activated protein kinase activation, and growth in rat aortic smooth muscle cells. 763 78

The activation state of the members of the mitogen-activated protein kinase family following photodynamic therapy (PDT) with benzoporphyrin derivative monoacid ring A was investigated using a naturally transformed murine keratinocyte cell line, Pam 212. PDT involves the use of photosensitizer molecules and a specific wavelength of visible light. The process of PDT generates singlet oxygen and other reactive oxygen intermediates (ROIs), and the cytotoxic effect of these ROIs is the basis for the use of PDT to treat cancer and psoriasis. PDT caused a strong dose- and time-dependent activation of both stress-activated protein kinase (SAPK) and p38 HOG1. The maximum activation of SAPK and p38 HOG1 occurred between 20 and 30 min following PDT treatment with 200 ng/ml benzoporphyrin derivative monoacid ring A and 2 J/cm2 of red light at 690 nm. In our system, PDT did not cause significant activation of extracellularly regulated kinase (ERK) 1 and ERK2. Under the same experimental conditions, ultraviolet light irradiation caused strong activation of SAPK and p38 HOG1 and minimum activation of ERK1 and ERK2 in Pam212 cells. A number of ROI scavengers were tested for their effect on PDT-induced SAPK and p38 HOG1 activation. Both L-histidine and N-acetyl-L-cysteine showed a significant inhibitory effect on PDT-induced SAPK and p38 HOG1 activation. This indicated that PDT-induced SAPK and p38 HOG1 activation may be partially mediated by ROI.
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PMID:Stimulation of stress-activated protein kinase and p38 HOG1 kinase in murine keratinocytes following photodynamic therapy with benzoporphyrin derivative. 890 Feb 2

Anthralin is a widely used, topical therapy for psoriasis. Anti-proliferative and anti-inflammatory properties of anthralin have been identified. Little is known, however, about differential sensitivities of targeted cell types and specific mechanisms of signaling pathway activation. We demonstrate that anthralin exerts potent effects on keratinocytes and mononuclear cells through strong induction of lipid peroxidation and JNK activation, a stress-induced signal transduction pathway. Lipid peroxidation was observed rapidly and half-maximal levels of lipid peroxidation were reached at a 10-fold lower concentration of anthralin for peripheral blood mononuclear cells vs normal keratinocytes. JNK activation was detected in peripheral blood mononuclear cells at a 40-fold lower anthralin dose compared with keratinocytes. For both cell types, selected inhibitors of lipid peroxidation prevented JNK activation. This study demonstrates that mononuclear leukocytes are markedly more sensitive than keratinocytes to anthralin-induced lipid peroxidation and JNK activation. We identify anthralin as a novel and potent inducer of JNK activation and demonstrate that this process is mediated, at least in part, by lipid peroxidation which is among the earliest and most proximate, membrane-related responses to anthralin yet described.
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PMID:Anti-psoriatic drug anthralin activates JNK via lipid peroxidation: mononuclear cells are more sensitive than keratinocytes. 1073 74

In normal epidermis, beta1 integrin expression is confined to the basal layer, whereas in hyperproliferative epidermis, integrins are also expressed in the suprabasal layers. Transgenic mice in which integrins are expressed suprabasally via the involucrin promoter have a sporadic psoriatic phenotype; however, the mechanism by which integrins contribute to the pathogenesis of psoriasis is unknown. We observed activation of mitogen-activated protein kinase (MAPK) in basal and suprabasal keratinocytes of human and transgenic mouse psoriatic lesions and healing mouse skin wounds, correlating in each case with suprabasal integrin expression. Phenotypically normal human and transgenic mouse epidermis did not contain activated MAPK. Transgene-positive keratinocytes produced more IL-1alpha than controls did, and keratinocyte MAPK could be activated by ligation of suprabasal integrins or treatment with IL-1alpha. Constitutive activation of MAPK increased the growth rate of human keratinocytes and delayed the onset of terminal differentiation, recreating many of the histological features of psoriatic epidermis. We propose that activation of MAPK by integrins, either directly or through increased IL-1alpha production, is responsible for epidermal hyperproliferation in psoriasis and wound healing, and that the sporadic phenotype of the transgenic mice may reflect the complex mechanisms by which IL-1 release and responsiveness are controlled in skin.
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PMID:A role for mitogen-activated protein kinase activation by integrins in the pathogenesis of psoriasis. 1151 26

Alefacept, an immunomodulatory recombinant fusion protein composed of the first extracellular domain of LFA-3 fused to the human IgG1 hinge, C(H)2, and C(H)3 domains, has recently been shown in phase II and III clinical trials to safely reduce disease expression in patients with chronic plaque psoriasis. Alefacept modulates the function of and selectively induces apoptosis of CD2(+) human memory-effector T cells in vivo. We have sought to gain further understanding of the mechanisms of action that influence the biological activity of alefacept and may contribute to its efficacy and patient responsiveness. Specifically evaluated is the ability of alefacept to activate intracellular signals mediated via CD2 and/or Fc gamma RIII (CD16). Experimentation using isoforms of alefacept engineered to have amino acid substitutions in the IgG1 C(H)2 domain that impact Fc gamma R binding indicate that alefacept mediates cognate interactions between cells expressing human CD2 and CD16 to activate cells, e.g., increase extracellular signal-regulated kinase phosphorylation, up-regulate cell surface expression of the activation marker CD25, and induce release of granzyme B. In the systems used, this signaling is shown to require binding to CD2 and CD16 and be mediated through CD16, but not CD2. Experimentation using human CD2-transgenic mice and isoforms of alefacept confirmed the requirement for Fc gamma R binding for detection of the pharmacological effects of alefacept in vivo. Thus alefacept acts as an effector molecule, mediating cognate interactions to activate Fc gamma R(+) cells (e.g., NK cells) to induce apoptosis of sensitive CD2(+) target cells.
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PMID:Alefacept, an immunomodulatory recombinant LFA-3/IgG1 fusion protein, induces CD16 signaling and CD2/CD16-dependent apoptosis of CD2(+) cells. 1197 Sep 90

Nerve growth factor induces innervation and epidermal hyperplasia in inflammatory skin diseases like psoriasis. Nerve growth factor production by keratinocytes is increased in the inflammatory lesions. Nerve growth factor induces histamine release from mast cells. We examined the in vitro effects of histamine on nerve growth factor production in human keratinocytes. Histamine enhanced nerve growth factor secretion, mRNA expression, and promoter activity in keratinocytes. Two TPA-response elements on the nerve growth factor promoter were responsible for the activation by histamine. Histamine enhanced transcriptional activity and DNA binding of activator protein 1 at the two TPA-response elements. It shifted the TPA-response-element-binding activator protein 1 composition from c-Jun homodimers to c-Fos/c-Jun heterodimers. Histamine transiently induced c-Fos mRNA expression, which was not detectable in unstimulated keratinocytes, whereas c-Jun mRNA expression was constitutive and was not altered by histamine. Histamine-induced enhancement of nerve growth factor secretion, promoter activity, activator protein 1 transcriptional activity, and c-Fos expression was suppressed by H1 antagonist pyrilamine, protein kinase C inhibitor calphostin C, and PD98059, an inhibitor of mitogen-activated protein kinase kinase 1. Histamine induced the translocation of protein kinase C activity from cytosol to membrane, which was suppressed by phospholipase C inhibitor U73122. It stimulated the phosphorylation of extracellular signal-regulated kinase, which was blocked by pyrilamine, calphostin C, and PD98059. These results suggest that histamine may enhance nerve growth factor production by inducing c-Fos expression in keratinocytes. These effects may be mediated by the H1-receptor-induced signaling cascade of phospholipase C-protein kinase C-mitogen-activated protein kinase kinase 1-extracellular signal-regulated kinase.
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PMID:Histamine enhances the production of nerve growth factor in human keratinocytes. 1292 17

TNFalpha is a crucial cytokine in the establishment and maintenance of inflammation in multiple autoimmune diseases. With the introduction of infliximab and etanercept, two injectable biologic TNFalpha blocking drugs are now available. Both are effective in the treatment of rheumatoid arthritis, reducing clinical inflammation and damage to bones. In addition, infliximab is FDA-approved for the treatment of Crohn's disease. More recent controlled trials have shown effectiveness for TNFalpha blockers in psoriasis, psoriatic arthritis, and ankylosing spondylitis. Further trials are underway in diverse inflammatory conditions including including uveitis, sarcoidosis, Behcet's syndrome, and graft versus host disease. Although the safety profile has been generally excellent, the rare development of reactivation tuberculosis, anti double-stranded DNA antibodies, or a demyelination syndrome point out the need for further close follow-up of treated patients. New formulations of recombinant anti-TNFalpha biologics undergoing clinical trials use modifications to reduce antigenicity, increase the half-life, and maintain or extend the efficacy of these agents. Future development of TNFalpha antagonists is turning to small molecule inhibitors. The inhibition of the TNFalpha signaling cascade is under study using blockers of the p38, JNK, and ERK kinases, and by antagonists of transcription factor NF-kappaB activation. The goal of this approach is to develop compounds that are orally available, have increased selectivity compared to generalized blockade of TNFalpha, yet are therapeutically useful for a range of chronic inflammatory diseases.
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PMID:TNFalpha as therapeutic target: new drugs, more applications. 1456 Nov 84

Cytokine PharmaSciences is developing semapimod (CNI-1493), a cytokine inhibitor and synthetic guanylhydrazone mitogen-activated protein kinase blocker, as a potential treatment for Crohn's disease and other inflammatory conditions. As of December 2001, a phase I study demonstrating the safety of the compound had been completed and phase II trials for psoriasis and Crohn's disease were ongoing. In April 2003, preclinical and early clinical studies were underway for a variety of indications, including congestive heart failure and pancreatitis.
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PMID:Semapimod. Cytokine. 1475 76

In order to study the relationship between insulin like growth factor-II (IGF-II) and interleukin-8 (IL-8) that are upregulated in psoriasis, we monitored IL-8 expression in IGF-II-treated human keratinocytes and explored the signaling pathways of IL-8 expression by IGF-II. IGF-II increased the IL-8 mRNA and protein levels in human keratinocytes. The upregulation of IL-8 expression by IGF-II was reduced by pretreatment with inhibitors of tyrosine kinase, Src, PI3-kinase, and ERK, but not by p38. Furthermore, IGF-II remarkably increased the DNA binding activities of NF-kappaB and AP-1, and the IL-8 promoter activity. However, cotransfection with IkappaB mutant blocked the IGF-II-induced IL-8 promoter activity. In addition, cotransfection with dominant negative MEK1 mutant, but not with dominant negative p38 mutant, blocked the IGF-II-induced IL-8 promoter activity. These results suggest that IGF-II is involved in the pathogenesis of psoriasis by inducing IL-8 gene expression through the tyrosine kinase-Src-ERK1/2-AP-1 pathway, and the PI3-kinase and NF-kappaB pathway.
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PMID:Differential regulation of IGF-II-induced IL-8 by extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinases in human keratinocytes. 1504 80

Psoriasis is a chronic, relapsing skin disease characterized by enhanced angiogenesis. The pathogenetic process resulting in hypervascularity remains to be further investigated. It has been reported that a potent angiogenic factor, vascular endothelial growth factor (VEGF) is overexpressed in psoriatic epidermis and that the level of insulin-like growth factor II (IGF-II) is significantly elevated in the tissue fluid and serum of the psoriatic lesion. We considered the possibility that IGF-II might function as a paracrine inducer of VEGF. Here, we demonstrated that exposure of HaCaT keratinocytes to IGF-II induced both mRNA and protein expression of VEGF through the MAP kinase (extracellular signal-regulated kinase (ERK2) pathway. Particularly, we determined that phosphorylation of ERK2 but not p38 and JNK1/2 was activated by IGF-II in a time-dependent manner. Additionally, we found that IGF-II treatment induced the expression of MDM2 through the MAP kinase pathway. Moreover, the increase of MDM2 resulted in decreased levels of p53 followed by increased expression of HIF-1alpha and VEGF. Taken together, these results suggest that IGF-II enhances the expression of VEGF in HaCaT cells by increasing HIF-1alpha levels.
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PMID:Insulin-like growth factor-II regulates the expression of vascular endothelial growth factor by the human keratinocyte cell line HaCaT. 1519 55


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