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)

The current study sought to define the molecular mechanisms involved in the cross talk between 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] and activators of PKC in the regulation of 25(OH)D(3) 24-hydroxlyase [24(OH)ase]. Transfection of the h24(OH)ase promoter construct [-5,500/-22 luciferase; vitamin D response elements at -294/-274 and -174/-151; AP-1 site at -1,167/-1,160] in vitamin D receptor (VDR)-transfected COS-7 cells resulted in strong activation by 1,25(OH)(2)D(3). In these cells, cotreatment with the PKC activator TPA and 1,25(OH)(2)D(3) yielded a 27-fold increase in luciferase activity, which was 2- to 3-fold greater than activation obtained with 1,25(OH)(2)D(3) alone (P < 0.05). Similar results were observed using LLCPK-1 kidney cells, suggesting that the previously observed enhancement of 1,25(OH)(2)D(3)-induced renal 24(OH)ase mRNA and activity by PKC activation occurs at the level of transcription. The functional cooperation between PKC activation and VDR was not found to be mediated by the AP-1 site in the h24(OH)ase promoter or by enhanced binding of GRIP or DRIP205 to VDR and was also not due to PKC-mediated phosphorylation of VDR on Ser(51). Our study demonstrates that, in LLCPK-1 kidney cells, the PKC enhancement of 1,25(OH)(2)D(3)-stimulated transcription may be due, in part, to an increase in VDR concentration. In addition, inhibitors of the MAPK pathway were found to decrease the TPA enhancement (P < 0.05). Because activation of MAPK has been reported to result in the phosphorylation of SRC-1 and in functional cooperation between SRC-1 and CREB binding protein, we propose that the potentiation of VDR-mediated transcription may also be mediated through changes in the phosphorylation of specific VDR coregulators.
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PMID:Integration of hormone signaling in the regulation of human 25(OH)D3 24-hydroxylase transcription. 1466 42

Repeated intermittent treatment with amphetamine (AMPH) induces both neurite outgrowth and enhanced AMPH-stimulated dopamine (DA) release in PC12 cells. We investigated the role of protein kinases in the induction of these AMPH-mediated events by using inhibitors of protein kinase C (PKC), mitogen activated protein kinase (MAP kinase) or protein kinase A (PKA). PKC inhibitors chelerythrine (100 nm and 300 nm), Ro31-8220 (300 nm) and the MAP kinase kinase inhibitor, PD98059 (30 micro m) inhibited the ability of AMPH to elicit both neurite outgrowth and the enhanced AMPH-stimulated DA release. The direct-acting PKC activator, 12-O-tetradecanoyl phorbol 13-acetate (TPA, 250 nm) mimicked the ability of AMPH to elicit neurite outgrowth and enhanced DA release. On the contrary, a selective PKA inhibitor, 100 micro m Rp-8-Br-cAMPS, blocked only the development of AMPH-stimulated DA release but not the neurite outgrowth. Treatment of the cells with acute AMPH elicited an increase in the activity of PKC and MAP kinase but not PKA. These results demonstrated that AMPH-induced increases in MAP kinase and PKC are important for induction of both the enhancement in transporter-mediated DA release and neurite outgrowth but PKA was only required for the enhancement in AMPH-stimulated DA release. Therefore the mechanisms by which AMPH induces neurite outgrowth and the enhancement in AMPH-stimulated DA release can be differentiated.
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PMID:Repeated amphetamine treatment induces neurite outgrowth and enhanced amphetamine-stimulated dopamine release in rat pheochromocytoma cells (PC12 cells) via a protein kinase C- and mitogen activated protein kinase-dependent mechanism. 1471 10

Surfactant protein A (SP-A), the most abundant pulmonary surfactant protein, plays a role in innate host defense and blocks the inhibitory effects of serum proteins on surfactant surface tension-lowering properties. SP-A mRNA and protein are downregulated by phorbol esters (TPA) via inhibition of gene transcription. We evaluated the TPA signaling pathways involved in SP-A inhibition in a lung cell line, H441 cells. TPA caused sustained phosphorylation of p44/42 mitogen-activated protein kinase (MAPK), p38 MAPK, and c-Jun-NH(2)-terminal kinase. An inhibitor of conventional and novel isoforms of protein kinase C (PKC) and two inhibitors of p44/42 MAPK kinase partially or completely blocked the inhibitory effects of TPA on SP-A mRNA levels. In contrast, inhibitors of conventional PKC-alpha and -beta, stress-activated protein kinases, protein phosphatases, protein kinase A, and the phosphatidylinositol 3-kinase pathway had no effect on the TPA-mediated inhibition of SP-A mRNA. TPA also stimulated the synthesis of c-Jun mRNA and protein in a time-dependent manner. Inhibitors of the p44/42 MAPK signaling pathway and PKC blocked the TPA-mediated phosphorylation of p44/42 MAPK and the increase in c-Jun mRNA. We conclude that TPA inhibits SP-A gene expression via novel isoforms of PKC, the p44/42 MAPK pathway, and the activator protein-1 complex.
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PMID:Signal transduction events involved in TPA downregulation of SP-A gene expression. 1475 51

PBK/TOPK is a recently identified 322 amino acid serine/threonine kinase that is phosphorylated during mitosis and may include p38 MAPK among its targets. Previous work has shown up-regulated expression of PBK/TOPK mRNA in a variety of tumor cell lines and fetal tissues, suggesting a role for this kinase in malignant cell proliferation. In this paper, PBK/TOPK protein expression was examined in a variety of primary hematologic neoplasms: PBK/TOPK was readily detected in 9 of 12 AML samples (75%), in 3 of 3 ALL samples, and in 1 sample each of a plasmacytoma and blastic type mantle cell lymphoma where it was strongly expressed. In contrast, PBK/TOPK was only weakly expressed in 2 samples of G-CSF-mobilized peripheral blood stem cells that were enriched in CD34+ progenitors by immunoselection. Furthermore, when HL-60 myeloid leukemic cells were differentiated with phorbol ester (TPA), PBK/TOPK protein expression was strongly down-regulated by 24 h. Under these same conditions, phosphorylated c-Myc was rapidly down-regulated (by 4 h), while the levels of cyclin D1 and phosphorylated p38 were constant. Notably, of 5 clinical samples that strongly expressed PBK/TOPK, 4 also strongly expressed phosphorylated c-Myc, while only 1 of 3 PBK/TOPK negative samples expressed phosphorylated c-Myc. These data show that PBK/TOPK protein is up-regulated in a variety of hematologic malignancies and may be involved in leukemic cell growth. Additional studies are warranted to determine if PBK/TOPK would be a valuable target for novel therapeutics. To this end, we also describe the derivation of clones of 293 (human embryonic kidney) cells, which carry an inducible kinase-defective mutant of PBK/TOPK. This model may be useful for studying the effects of down-regulated PBK/TOPK function.
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PMID:Protein expression of PDZ-binding kinase is up-regulated in hematologic malignancies and strongly down-regulated during terminal differentiation of HL-60 leukemic cells. 1475 41

It has been widely shown that many plant-derived compounds present significant anti-inflammatory effects. For this reason, they represent potential molecules for the development of new drugs, especially designed for the treatment and/or control of chronic inflammatory states such as rheumatism, asthma, inflammatory bowel diseases, atherosclerosis, etc. This review focuses on the naturally-occurring compounds with anti-inflammatory properties and attempts to correlate their actions with the modulation of cytokines and associated intracellular signalling pathways; it continues the review published in the November, 2003 issue of Planta Medica. Abbreviations. AP-1:activator protein-1 CCR1:chemokine receptor 1 CINC-1:cytokine-induced neutrophil chemoattractant 1 COX:cyclooxygenase EGCG:(-)-epigallocatechin gallate ELAM-1:endothelial-leukocyte adhesion molecule-1 ERK:extracellular signal-regulated kinase GRO:growth-related oncogene HUVEC:human umbilical vein endothelial cells ICAM-1:intercellular adhesion molecule-1 IFN:interferon IL:interleukin iNOS:inducible nitric oxide synthase IRA:the natural interleukin receptor activation JAK:janus kinase JNK:c-Jun NH2-terminal kinase LPS:lipopolysaccharide MAPK:mitogen-activated protein kinases MCP:monocyte chemotactic protein MHC:major histocompatibility complex MIP:macrophage inflammatory protein MMP:matrix metalloproteinases MPO:myeloperoxidase NF-kappaBnuclear factor kappa B NO:nitric oxide PAF:platelet aggregation factor PGEE:prostaglandin PK:protein kinase PMA/TPA:phorbol myristate acetate RANTES:regulated upon activation normal T-cell expressed and secreted TGF-beta:transforming growth factor-beta TNFalpha:tumour necrosis factor VCAM-1:vascular cell adhesion molecule-1
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PMID:Anti-inflammatory compounds of plant origin. Part II. modulation of pro-inflammatory cytokines, chemokines and adhesion molecules. 1499 84

The dual-specificity phosphatase Pyst2-L was found to be highly expressed in leukocytes derived from AML and ALL patients as well as in certain other solid tumors and lymphoblastoid cell lines. Recently, by use of the 5'-RNA ligation-mediated rapid amplification of cDNA ends (5'-RLM-RACE) technique, we sequenced and cloned the entire open reading frame (ORF) of Pyst2-L. In the present study we determined the effect of exogenous overexpression on Erk1/2 phosphorylation. It was demonstrated that overexpression of this phosphatase in HEK293 cells reduced the basal levels of phospho-Erk1/2 as compared to the same cells transfected with the wild-type vector. This reduction was concomitant with a growth retardation of the Pyst2-L-transfected cells. Treating Pyst2-L transfected cells with known activators of the MAPK signaling cascade such as TPA or stimulating them by serum, it was demonstrated that the up regulation of phospho-Erk1/2, caused by these activators, was only partially suppressed by the over expression of the Pyst2-L phosphatase in these cells. These results together with our previous ones showing that the TPA-induced up regulation of Pyst2-L mRNA was only partially inhibited by the use of a specific Mek1/2 inhibitor, lead us to ask whether the Pyst2-L phosphatase has a monogamous relationship with the Erk2 protein. To answer this question, we employed the pull-down method and showed that in addition to phospho-Erk1/2, recombinant Pyst2-L binds the phospho-JNK protein. These findings may raise new perspectives regarding the role played by this phosphatase in malignant cells and in activation processes.
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PMID:Does the dual-specificity MAPK phosphatase Pyst2-L lead a monogamous relationship with the Erk2 protein? 1508 39

BCL2 family members are subject to regulation at multiple levels, providing checks on their ability to contribute to tumorigenesis. However, findings on post-translational BCL2 phosphorylation in different systems have been difficult to integrate. Another antiapoptotic family member, MCL1, exhibits a difference in electrophoretic mobility upon phosphorylation induced by an activator of PKC (12-O-tetradecanoylphorbol 13-acetate; TPA) versus agents that act on microtubules or protein phosphatases 1/2A. A multiple pathway model is now presented, which demonstrates that MCL1 can undergo distinct phosphorylation events - mediated through separate signaling processes and involving different target sites - in cells that remain viable in the presence of TPA versus cells destined to die upon exposure to taxol or okadaic acid. Specifically, TPA induces phosphorylation at a conserved extracellular signal-regulated kinase (ERK) site in the PEST region (Thr 163) and slows turnover of the normally rapidly degraded MCL1 protein; however, okadaic acid and taxol induce ERK-independent MCL1 phosphorylation at additional discrete sites. These findings add a new dimension to our understanding of the complex regulation of antiapoptotic BCL2 family members by demonstrating that, in addition to transcriptional and post-transcriptional regulation, MCL1 is subject to multiple, separate, post-translational phosphorylation events, produced in living versus dying cells at ERK-inducible versus ERK-independent sites.
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PMID:MCL1 is phosphorylated in the PEST region and stabilized upon ERK activation in viable cells, and at additional sites with cytotoxic okadaic acid or taxol. 1524 87

Cholesterol has been recently suggested to regulate the early steps of keratinocyte differentiation through lipid rafts. In many cell types, depletion of cholesterol activates signaling proteins like epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), or extracellular signal-regulated kinase (ERK) known to affect cell differentiation. In this study, we explored the effects of cholesterol depletion on the phenotype of cultured keratinocytes, using a treatment with methyl-beta-cyclodextrin (MbetaCD) to extract cholesterol and a treatment with lovastatin to inhibit cholesterol neosynthesis. Analysis of the expression of differentiation marker genes in early differentiating confluent cultures reveals that cholesterol depletion induces downregulation of keratin 14 (K14) and keratin 10 (K10) and upregulation of involucrin. MbetaCD treatment induces phosphorylation of EGFR, HER2, and ERK, but not HER3. Inhibition of EGFR with PD153035 impairs the MbetaCD-induced phosphorylation of EGFR, HER2, and ERK, but does not impair the alteration of K14, K10, or involucrin gene expression, indicating that other signaling proteins regulate this phenomenon. p38 has been suggested to regulate the expression of involucrin during keratinocyte differentiation. We found that MbetaCD treatment induces a prolonged phosphorylation of p38 in general and p38alpha in particular. An inhibition of p38 with PD169316 impairs the upregulation of involucrin mRNAs by a treatment with MbetaCD, but not by a p38delta-activating TPA treatment, which might suggest that cholesterol depletion alters involucrin gene expression through activation of p38alpha/beta.
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PMID:Cholesterol depletion upregulates involucrin expression in epidermal keratinocytes through activation of p38. 1530 97

In a search for compounds inhibiting the inducible TNF-alpha promoter activity in T cells, a new spiro-compound, designated oxaspirodion, was isolated from fermentations of the ascomycete Chaetomium subspirale. Oxaspirodion inhibited TNF-alpha promoter-driven luciferase reporter gene expression with an IC50 value of 2.5 microg/ml (10 microM) in TPA/ionomycin-stimulated Jurkat T cells. Studies on the mode of action of the compound revealed that the inhibition of the TNF-alpha promoter activity is caused by an inhibition of the phosphorylation of the ERK1/2 kinases. In addition, oxaspirodion inhibited the activation of the transcription factor NF-kappaB, which is involved in the inducible expression of many proinflammatory genes.
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PMID:Inhibition of inducible TNF-alpha expression by oxaspirodion, a novel spiro-compound from the ascomycete Chaetomium subspirale. 1549 78

Tight junctions as an epithelial barrier against paracellular diffusion have mainly been investigated on the protein level with particular respect to subcellular localization. In this study, real-time PCR has been established to investigate the influence of protein kinase C (PKC) modulation on the transcription of tight junction elements occludin and ZO-1 in the cell line T84. Activation of PKC by the phorbol ester TPA induced ZO-1 and occludin transcription, whereas PKC inhibition lead to decreased expression levels. Activation of PKC exerted its effect on transcript level directly. PKC signal was partially transduced via MEK1/MEK2 but depended strongly on MAPK independent pathways probably involving nuclear localized PKC, whereas p38 signaling was not implicated. TPA induced loss of function concomitant with a dislocation of ZO-1 and occludin could be prevented by inhibition of MEK1 by PD98059. Overall ZO-1 and occludin seem to be identically regulated in colonic epithelium on the transcript level.
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PMID:Influence of protein kinase C on transcription of the tight junction elements ZO-1 and occludin. 1562 22


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