Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To investigate how cardiac myocytes recover from a brief period of ischemia, we used a metabolic inhibition (MI) model, one of the in vitro ischemic models, of chick embryo ventricular myocytes, and examined the induction of immediate-early (IE) genes mRNAs and the activity of mitogen-activated protein (MAP) kinase. We performed Northern blot analysis to study the expression of c-jun, c-fos, and c-myc mRNAs during MI using 1 mM NaCN and 20 mM 2-deoxy-d-glucose, and also during the recovery from MI of 30 min. The c-fos mRNA was induced transiently at 30 and 60 min during the recovery. The expression of c-jun mRNA was significantly augmented at 30, 60, 90, and 120 min during the recovery (3.0-, 4.7-, 2.4-, and 1.9-fold induction, respectively) and so did the expression of c-myc mRNA (1.4-, 1.7-, 1.8-, and 2.0-fold induction, respectively). In contrast, the levels of these mRNAs remained unchanged during MI. The electrophoretic mobility shift assay revealed that AP-1 DNA binding activity markedly increased at 120 min during the recovery. When the cells were pretreated with protein kinase C (PKC) inhibitors, 100 microM H-7 or 1 microM staurosporine, the induction of c-jun mRNA at 60 min during the recovery was markedly suppressed (95 or 82% reduction, respectively). The c-jun induction was partially inhibited when the cells were treated with 2 mM EGTA during MI and the recovery (42% reduction). MAP kinase activity quantified with in-gel kinase assay was unchanged during MI, but significantly increased at 5, 10, and 15 min during the recovery (3.0-, 4.1-, and 3.4-fold increase, respectively). S6 kinase activity was also augmented significantly at 15 min during the recovery. Thus, these data suggest that IE genes as well as MAP kinase may play roles in the recovery process of cardiac myocytes from MI, and that the augmentation of c-jun expression needs the activation of PKC and to some extent, [Ca2+]i.
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PMID:Immediate-early gene induction and MAP kinase activation during recovery from metabolic inhibition in cultured cardiac myocytes. 761 38

The ability of the receptor for the hematopoietic cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) to function in non-hematopoietic cells is unknown. NIH3T3 fibroblasts were transfected with cDNAs encoding the alpha and beta subunit of the human GM-CSF receptor and a series of stable transformants were isolated that bound GM-CSF with either low (KD = 860 - > 1000 pM) or high affinity (KD = 20-80 pM). Low affinity receptors were not functional. However, the reconstituted high affinity receptors were found to be capable of activating a number of signal transduction pathways, including tyrosine kinase activity, phosphorylation of Raf-1, and the transient induction of c-fos and c-myc mRNAs. The activation of protein tyrosine phosphorylation by GM-CSF in NIH3T3 cells was rapid (< 1 min) and transient (peaking at 5-20 min) and resulted in the phosphorylation of proteins of estimated molecular weights of 42, 44, 52/53 and 58-60 kDa. Some of these proteins co-migrated with proteins from myeloid cells that were phosphorylated on tyrosine residues in response to GM-CSF. In particular, p42 and p44 were identified as mitogen-activated protein kinases (MAP kinases), and the phosphorylation on tyrosine residues of p42 and p44 MAP kinases occurred at the same time as the phosphorylation of Raf-1. However, despite evidence for activation of many mitogenic signal transduction molecules, GM-CSF did not induce significant proliferation of transfected NIH3T3 cells. These results suggest that murine fibroblasts contain signal transducing molecules that can effectively interact with the human GM-CSF receptor, and that are sufficient to activate at least some of the same signal transduction pathways this receptor activates in myeloid cells, including activation of one or more tyrosine kinase(s). However, the level of activation of signal transduction is either below a threshold of necessary activity or at least one mitogenic signal necessary for proliferation is missing.
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PMID:The human granulocyte-macrophage colony-stimulating factor receptor is capable of initiating signal transduction in NIH3T3 cells. 768 77

The neuro-intestinal peptide hormone cholecystokinin (CCK)/gastrin has been suggested to have a trophic effect on gastro-intestinal tract in vivo as well as in vitro. In the present study, the human CCK-B/gastrin receptor was expressed in mouse NIH3T3 fibroblasts to investigate the molecular basis of signal transduction pathway of the guanine nucleotide regulatory protein (G protein)-coupled receptor. Human CCK-B/gastrin receptor expressed in NIH3T3 cells coupled efficiently to phosphoinositide hydrolysis and mobilization of intracellular Ca2+, and transduced mitogenic signals assessed by [3H]thymidine incorporation in a dose-dependent manner. Moreover, CCK-8 or gastrin I alone promoted the cell growth in serum-free medium. CCK-8 induced tyrosine phosphorylation of several protein species. Among them, mitogen-activated protein (MAP) kinase was tyrosine phosphorylated and activated in response to CCK-8, as was induced by platelet-derived growth factor (PDGF). In contrast, tyrosine phosphorylation of p125FAK (focal adhesion kinase) was induced by CCK-8 but not by PDGF. CCK-8 as well as gastrin I induced the expression of early responsive genes such as c-fos and c-myc. These results suggest that CCK-B/gastrin receptors might transmit mitogenic signals by cross-talking with the tyrosine kinase cascades.
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PMID:Cholecystokinin-B/gastrin receptor signaling pathway involves tyrosine phosphorylations of p125FAK and p42MAP. 810 29

Fibroblast growth factors (FGF) elicit biological effects by binding to high affinity cell-surface receptors and activation of receptor tyrosine kinase. We previously reported that two NIH/3T3 derivatives, NR31 and NR33 (NR cells), express high levels of full-length FGF-1 and exhibit a complete spectrum of transformed phenotype. In the present study, we report that NR cells respond to the mitogenic stimulation of truncated FGF-1 but not to the full-length FGF-1. Incubation of the NR cells with either form of FGF-1 resulted in its binding to cell-surface FGF receptors, activation of mitogen-activated protein (MAP) kinase, and induction of c-fos and c-myc. These data demonstrate that the FGF receptor-mediated, MAP kinase-dependent signaling pathway is not defective in the NR cells. Our data further suggest that the activation of MAP kinase in response to full-length FGF-1 is not sufficient for mitogenesis. Subcellular distribution of exogenously added FGF-1 demonstrated that full-length FGF-1 fails to translocate to the nuclei of NR31 cells. Although the full-length FGF-1 was detected in the nuclear fractions of both NIH/3T3 and NR33 cells, its half-life is much shortened in NR33 than in NIH/3T3 cells. These observations suggest that non-responsiveness of the two NR cell lines may be due to defectiveness at different steps of nuclear translocation mechanism of FGF-1.
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PMID:Fibroblast variants nonresponsive to fibroblast growth factor 1 are defective in its nuclear translocation. 946 16

In response to oxidant stress, the cardiovascular system is known to express a number of genes, which could occur owing to the participation of mitogen-activated protein kinases such as MAPKs, ERK and JNK (SAPK) followed by stimulation of at least two well-defined transcription factors NF-KB and AP-1 (c-Fos and c-Jun). Oxidants activate cytosolic and membrane-bound PLA2 activities with the subsequent production of AA metabolites such as HETEs, which subsequently stimulate ERK and JNK (SAPK) activities leading to the activation of transcriptional factors and the ultimate stimulation of the transcription of several mitogen-stress-responsive genes. LacCer, a ceramide analogue present in atherosclerotic plaques, has been found to induce proliferation of aortic smooth muscle cells. LacCer is involved in Ras-GTP loading, activation of kinase cascades (MEK, Raf, p44 MAPK) and c-fos expression. TNF-alpha, on the other hand, induces c-fos, c-myc and c-jun expression. Recent investigations link ceramide and its analogues to the extracellular signal-regulated kinase (ERK) cascade, stress-activated protein kinase-c-Jun kinase (SAPK/JNK) cascade and apoptotic responses. These critical steps in the signalling pathways are sensitive to intracellular thiol-redox and protease(s)-antiprotease(s) status, both of which can be modified by oxidants. Because mobilisation of intracellular Ca2+ caused by a variety of signals also plays a role in the activation of the signalling pathways, an important aspect of future work will be to ascertain the roles of oxidants and Ca2+ individually and in combination in the activation of the signalling pathways. The following two important questions also deserve future attention: (1) How does NF-kB shield cells from apoptotic death? and (2) By what mechanisms does the activated NF-kB cause cellular transformation? Furthermore, the role of AP-1 acting as transcriptional activator seems clear, but the target genes remain to be defined.
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PMID:Oxidant-mediated activation of mitogen-activated protein kinases and nuclear transcription factors in the cardiovascular system: a brief overview. 988 18

Heme oxygenase (HO) is responsible for the physiological breakdown of heme into equimolar amounts of biliverdin, carbon monoxide, and iron. Three isoforms (HO-1, HO-2, and HO-3) have been identified. HO-1 is ubiquitous and its mRNA and activity can be increased several-fold by heme, other metalloporphyrins, transition metals, and stimuli that induce cellular stress. HO-1 is recognized as a major heat shock/stress response protein. Recent work from our laboratory has demonstrated several potential consensus regulatory elements in the 5'-untranslated region (UTR) of HO-1, including activator protein 1 (AP-1), metal responsive element (MRE), oncogene c-myc/max heterodimer binding site (Myc/Max), antioxidant response element (ARE), and GC box binding (Sp1) sites. Using deletion-reporter gene constructs, we have mapped sites that mediate the arsenite-dependent induction of HO-1, and we have shown that components of the extracellular signal-regulated kinase (ERK) and p38 (a homologue of the yeast HOG1 kinase), but not c-jun N-terminal kinase (JNK), mitogen-activated protein (MAP) kinase pathways are involved in arsenite-dependent upregulation. In contrast, HO-2 is present chiefly in the brain and testes and is virtually uninducible. HO-3 has very low activity; its physiological function probably involves heme binding. Products of the HO reaction have important effects: carbon monoxide is a potent vasodilator, which is thought to play a key role in the modulation of vascular tone, especially in the liver under physiological conditions, and in many organs under "stressful" conditions associated with HO-1 induction. Biliverdin and its product bilirubin, formed in most mammals, are potent antioxidants. In contrast, "free" iron increases oxidative stress and regulates the expression of many mRNAs (e.g., DCT-1, ferritin, and transferrin receptor) by affecting the conformation of iron regulatory protein (IRP)-1 and its binding to iron regulatory elements (IREs) in the 5'- or 3'-UTRs of the mRNAs.
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PMID:Heme oxygenase: recent advances in understanding its regulation and role. 1051 65

The kidneys are the primary organ for the accumulation and toxicity of inorganic mercury. In these studies the molecular response of precision-cut rabbit renal cortical slices to low levels of inorganic mercury was examined. Cortical slices (275 microm) were obtained from 1.0 kg NZW rabbits and exposed to mercuric chloride [Hg(II)] at concentrations of 0.01-10 microM for 2-8 h. Overt cytotoxicity, as assessed by intracellular K(+) levels, was not observed following exposure to these concentrations of Hg(II). However, an induction of heme-oxygenase-1 (Hsp32) was seen following a 2-h challenge to Hg(II). A dose-dependent induction of the DNA binding activity of the AP-1 transcription factor after 4 h of Hg(II) exposure correlated with a dose-dependent enhancement of c-jun gene expression following 2 h of Hg(II) exposure. Additionally, an increase in phosphorylated c-Jun NH(2)-terminal protein kinase (JNK) was observed following 2 h of Hg(II) exposure. These results suggest activation of the mitogen-activated protein (MAP) signal transduction pathway, specifically the c-Jun NH(2)-terminal protein kinase (JNK) pathway. No changes were observed, however, in the DNA binding activity of ATF2 and Elk-1, transcription factors involved in both the JNK and p38 pathways of MAP signal transduction, nor in the gene expression of c-myc. This selectivity of alterations in molecular signaling suggests an acute response in signal transduction, specifically activation of the JNK pathway in renal tissue following exposure to nanomolar concentrations of Hg(II).
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PMID:Selective activation in the MAPK pathway by Hg(II) in precision-cut rabbit renal cortical slices. 1054 60

In cultured chick skeletal muscle cells loaded with Fura-2, the tyrosine kinase inhibitors herbimycin A and genistein abolished both the fast inositol 1,4,5-trisphosphatedependent Ca(2+) release from internal stores and extracellular Ca(2+) influx induced by 1alpha, 25(OH)(2)-vitamin D(3) (1alpha,25(OH)(2)D(3)). Daidzein, an inactive analog of genistein, was without effects. Tyrosine phosphatase inhibition by orthovanadate increased cytosolic Ca(2+). Anti-phosphotyrosine immunoblot analysis revealed that 1alpha, 25(OH)(2)D(3) rapidly (0.5-10 min) stimulates in a concentrationdependent fashion (0.1-10 nm) tyrosine phosphorylation of several myoblast proteins, among which the major targets of the hormone could be immunochemically identified as phospholipase Cgamma (127 kDa), which mediates intracellular store Ca(2+) mobilization and external Ca(2+) influx, and the growth-related proteins mitogen-activated protein (MAP) kinase (42/44 kDa) and c-myc (65 kDa). Genistein suppressed the increase in phosphorylation and concomitant elevation of MAPK activity elicited by the sterol. Both genistein and the MAPK kinase (MEK) inhibitor PD98059 abolished stimulation of DNA synthesis by 1alpha,25(OH)(2)D(3). The sterol-induced increase in tyrosine phosphorylation of c-myc, a finding not reported before for cell growth regulators, was totally suppressed by the specific Src inhibitor PP1. These results demonstrate that tyrosine phosphorylation is a previously unrecognized mechanism involved in 1alpha,25(OH)(2)D(3) regulation of Ca(2+) homeostasis in hormone target cells. In addition, the data involve tyrosine kinase cascades in the mitogenic effects of 1alpha, 25(OH)(2)D(3) on skeletal muscle cells.
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PMID:Involvement of tyrosine kinase activity in 1alpha,25(OH)2-vitamin D3 signal transduction in skeletal muscle cells. 1096 10

This article reviews recent results of studies aiming to elucidate modes of integrating signals initiated in ACTH receptors and FGF2 receptors, within the network system of signal transduction found in Y1 adrenocortical cells. These modes of signal integration should be central to the mechanisms underlying the regulation of the G0-->G1-->S transition in the adrenal cell cycle. FGF2 elicits a strong mitogenic response in G0/G1-arrested Y1 adrenocortical cells, that includes a) rapid and transient activation of extracellular signal-regulated kinases-mitogen-activated protein kinases (ERK-MAPK) (2 to 10 min), b) transcription activation of c-fos, c-jun and c-myc genes (10 to 30 min), c) induction of c-Fos and c-Myc proteins by 1 h and cyclin D1 protein by 5 h, and d) onset of DNA synthesis stimulation within 8 h. ACTH, itself a weak mitogen, interacts with FGF2 in a complex manner, blocking the FGF2 mitogenic response during the early and middle G1 phase, keeping ERK-MAPK activation and c-Fos and cyclin D1 induction at maximal levels, but post-transcriptionally inhibiting c-Myc expression. c-Fos and c-Jun proteins are mediators in both the strong and the weak mitogenic responses respectively triggered by FGF2 and ACTH. Induction of c-Fos and stimulation of DNA synthesis by ACTH are independent of PKA and are inhibited by the PKC inhibitor GF109203X. In addition, ACTH is a poor activator of ERK-MAPK, but c-Fos induction and DNA synthesis stimulation by ACTH are strongly inhibited by the inhibitor of MEK1 PD98059.
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PMID:Proliferative signaling initiated in ACTH receptors. 1100 13

Endostatin is a potent endogenous angiogenesis inhibitor that induces regression of tumors in mice. Neither an extracellular receptor for endostatin nor intracellular signals that result in the regression of tumor vascular beds have been identified. We demonstrate that endostatin, but not angiostatin, at comparable concentrations to those used in in vivo animal trials, rapidly down-regulates many genes in exponentially growing endothelial cells. These include immediate early response genes, cell cycle-related genes, and genes regulating apoptosis inhibitors, mitogen-activated protein kinases, focal adhesion kinase, G-protein-coupled receptors mediating endothelial growth, a mitogenic factor, adhesion molecules, and cell structure components. Suppression of both apoptosis inhibitors and cell proliferation genes may have a limited contribution to the antiangiogenesis process because endostatin induces neither apoptosis nor growth inhibition, unless studied under reduced serum conditions. In contrast, the antimigratory effect of endostatin was rapid and potent even under serum-supplemented conditions. Endostatin caused gene suppression and migration arrest exclusively in endothelial cells, most profoundly in microvascular endothelial cells. The c-myc null fibroblasts obtained by targeted homologous recombination showed an attenuated migration rate compared with isogenic parental cells, whereas the introduction of the c-myc gene into endothelial cells abrogated the antimigratory effect of endostatin. Inhibition of E-box-driven transcription by overexpressing max or mad suppressed endothelial migration. Thus, rapid down-regulation of genes by endostatin neither restores proliferating endothelial cells to their resting states nor induces apoptosis; rather, it potently inhibits endothelial cell migration partly via suppression of c-myc expression.
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PMID:Antiangiogenesis signals by endostatin. 1129 66


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