Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Ras/Raf/MAP kinase (ERK) pathway is a major signaling pathway induced by growth factors in mammalian cells. Two other types of mammalian MAP kinases, JNK (SAPK) and p38 (RK, CSBP), are induced by environmental stress. Although the immediate-early gene, egr-1, is induced by growth factors, cytokines, differentiation signals and DNA damaging agents, less is known about its induction by environmental stress and the mechanism involved. Here we report that in NIH3T3 cells, egr-1 is induced by various stress treatments such as heat shock, sodium arsenite, ultraviolet (U.V.) radiation, and anisomycin. p38 and JNK1, but not ERK2, were activated by these stress treatments. Induction of egr-1 by anisomycin is inhibited by a specific inhibitor of p38, SB 203580. We also show that p38 and JNK1 activated by their upstream kinases induce egr-1 promoter activity through activation of the ternary complex factor, Elk-1. The stress treatments also lead to an increase in Egr-1 protein phosphorylation and its DNA binding activity. Together, our data suggest that induction of egr-1 gene by growth factors and stress are mediated through different subgroups of MAP kinases which may also differentially affect egr-1 function on its target genes.
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PMID:Stress-induced immediate-early gene, egr-1, involves activation of p38/JNK1. 967 12

The effects of hypo- and hyper-osmotic shock on endogenous MAP-kinase activities and MKP-1 and c-jun mRNA levels were studied in H4IIE rat hepatoma cells. In presence of vanadate hypo-osmolarity stimulated a rapid and sustained activation of MAP-kinases (Erk-2, JNK-2 and p38). In the absence of vanadate a hypo-osmotic MAP-kinase response was not detectable. Hyper-osmolarity stimulated a delayed and transient MAP-kinase activation and vanadate was not required for its detection. Vanadate, however, amplified the hyper-osmotic MAP-kinase stimulation. c-jun and MKP-1 mRNA levels were maximal after 0.5-1 h of hypo-osmotic exposure and returned towards basal levels within 2 h, whereas the hyper-osmotic induction of c-jun and MKP-1 mRNA was delayed. Vanadate was not required for the aniso-osmotic effects on MKP-1 and c-jun mRNA levels. Whereas the hyper-osmolarity-induced c-jun mRNA accumulation returned towards basal levels within 8 h, MKP-1 mRNA was still highly expressed at this time point. The role of MAP-kinases for the induction of aniso-osmolarity-induced gene expression and the potential importance of MKP-1 for termination of aniso-osmotic MAP-kinase activation are discussed.
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PMID:Osmotic regulation of MAP-kinase activities and gene expression in H4IIE rat hepatoma cells. 968 15

The two MAP kinases JNK and ERK direct distinct cellular activities even though they share a number of common substrates, including several transcription factors. Here we have compared JNK and ERK signalling during PC12 cell differentiation and investigated how activation of c-Jun by the MAPKs contributes to this cellular response. Exposure to nerve growth factor, or expression of constitutively active MEK1-two treatments which cause differentiation of PC12 cells into a neuronal phenotype-result in activation of ERK-type MAP kinases and phosphorylation of c-Jun on several sites including Ser63 and Ser73. Constitutively activated c-Jun, which mimics the MAPK-phosphorylated form of the protein, can induce neuronal differentiation of PC12 cells independently of upstream signals. Conversely, expression of dominant-negative c-JunbZIP prevents neurite outgrowth induced by activated MEK1. Activation of MEKK1, which stimulates the JNK pathway, is not sufficient for PC12 cell differentiation but can induce apoptosis. However, neurite outgrowth is triggered when c-Jun is co-expressed with activated MEKK1 or SEK1. Consistently, MEK-induced ERK activation in PC12 cells induces c-Jun expression, while JNK signalling does not. Therefore, dual input of expression and phosphorylation of c-Jun provided by the ERK pathway is required to direct neuronal differentiation in PC12 cells.
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PMID:Differential regulation of c-Jun by ERK and JNK during PC12 cell differentiation. 968 8

The MAP kinase phosphatase 1 (MKP-1), a dual serine-threonine phosphatase, inactivates the MAP kinases ERK and JNK/SAPK which are involved in neuronal survival and neuronal cell death following injury and degenerative stimuli. We have studied by immunocytochemistry whether regulation of MKP-1 is part of the cell-body response following nerve fiber transection. The expression of MKP-1 was investigated in axotomized neurons of the corpus mamillaris (CMm) and substantia nigra pars compacta (SNC) following transection of the mamillo-thalamic tract (MT) and the medial forebrain bundle (MFB), respectively. In contrast to the surviving CMm neurons, the vast majority of SNC neurons undergoes cell death following axotomy. MKP-1 immunoreactivity which is absent in untreated adult rats, appeared in CMm neurons 24 h following MT transection, reached a maximum after 2 days and persisted in a substantial proportion of CMm neurons until 20 days, the end of observation period. In contradistinction, MKP-1 could not be detected in the SNC neurons. MKP-1 immunoreactivity was virtually restricted to the nuclei of neurons. Subcutaneous injection of the immunosuppressant FK506 that protects axotomized SNC neurons against neuronal cell death, enhanced the expression of MKP-1 in CMm, but failed to do so in SNC neurons. The selective expression of MKP-1 in CMm is the first finding on a different regulation of components in the stress kinase signal pathway in surviving vs. degenerating axotomized neurons.
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PMID:MAP kinase phosphatase 1 is expressed and enhanced by FK506 in surviving mamillary, but not degenerating nigral neurons following axotomy. 972 83

p38 MAP kinase (p38) and JNK have been described as playing a critical role in the response to a variety of environmental stresses and proinflammatory cytokines. It was recently reported that hematopoietic cytokines activate not only classical MAP kinases (ERK), but also p38 and JNK. However, the physiological function of these kinases in hematopoiesis remains obscure. We found that all MAP kinases examined, ERK1, ERK2, p38, JNK1, and JNK2, were rapidly and transiently activated by erythropoietin (Epo) stimulation in SKT6 cells, which can be induced to differentiate into hemoglobinized cells in response to Epo. Furthermore, p38-specific inhibitor SB203580 but not MEK-specific inhibitor PD98059 significantly suppressed Epo-induced differentiation and antisense oligonucleotides of p38, JNK1, and JNK2, but neither ERK1 nor ERK2 clearly inhibited Epo-induced hemoglobinization. However, in Epo-dependent FD-EPO cells, inhibition of either ERKs, p38, or JNKs suppressed cell growth. Furthermore, forced expression of a gain-of-function MKK6 mutant, which specifically activated p38, induced hemoglobinization of SKT6 cells without Epo. These results indicate that activation of p38 and JNKs but not of ERKs is required for Epo-induced erythroid differentiation of SKT6 cells, whereas all of these kinases are involved in Epo-induced mitogenesis of FD-EPO cells.
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PMID:Activation of p38 MAP kinase and JNK but not ERK is required for erythropoietin-induced erythroid differentiation. 973 Oct 42

The influence of cell hydration and taurine on the heat shock response was studied in primary rat hepatocytes. Heat-induced accumulation of inducible heat shock protein 70 (HSP70) mRNA and protein was increased under hypo-osmotic conditions. In contrast, hyper-osmotic exposure blocked the HSP70 response during an 8-hour recovery, and this was paralleled by a reduction of overall protein synthesis and an impairment of thermotolerance. Taurine counteracted the hyper-osmotic inhibition of heat-induced HSP70 expression, but increased overall protein synthesis only slightly. A rapid and transient activation of the stress-activated protein kinase, JNK-2, was triggered by hyper-osmolarity, whereas the JNK-2 response to hypo-osmolarity was delayed. JNK-2 activation in response to heat was suppressed by hypo-osmolarity, but was markedly increased under hyper-osmotic conditions. The latter effect was blocked by taurine. A pronounced induction of the mRNA for the MAP-kinase phosphatase, MKP-1, in response to heat was observed during hypo- and normo-osmolarity, but no MKP-1 induction was found under hyper-osmotic conditions, although hyper-osmolarity itself led to accumulation of small levels of MKP-1 mRNA. Also, the block of heat-induced MKP-1 mRNA expression by hyper-osmolarity was abolished in the presence of taurine. The data provide evidence for a role of cellular hydration and taurine in the protection of liver parenchymal cells against heat injury via regulation of HSP70 expression and the balance between JNK-2 and MKP-1 activity.
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PMID:Osmotic regulation of the heat shock response in primary rat hepatocytes. 973 72

MAPK pathways transduce a broad variety of extracellular signals into cellular responses. Despite their pleiotropic effects and their ubiquitous distribution, surprisingly little is known about their involvement in the communication network of nerve cells. As a first step to elucidate the role of MAPK pathways in neuronal signalling, we studied the distribution of SAPK alpha/JNK2, SAPK beta/JNK3, and SAPK gamma/JNK1, three isoforms of SAPK/JNK, a stress-activated MAPK subfamily. We compared the mRNA localisation of the three main isoforms in the adult and developing rat brain using in situ hybridisation. In the adult brain, SAPK alpha and beta were widely but heterogeneously distributed, reproducing the pattern of a probe that does not discriminate the isoforms. Differently, high labelling for the SAPK gamma probe was exclusively localised in the endopiriform nucleus and medial habenula. Intermediate staining was detected in the hippocampus. During post-natal development, SAPK beta showed the same localisation as in the adult. Nevertheless, the semi-quantitative analysis of optical densities showed significantly different mRNA levels. In the adult, SAPK gamma signal was weak, whereas in newborn rats the labelling was intense and widely distributed. SAPK gamma mRNA levels decreased during development, to reach the low signals detected in the adult. These results suggest that in the central nervous system SAPK-type MAP kinases perform significant physiological functions which are particularly relevant during post-natal development. The distinct distribution patterns of SAPK isoforms in the adult rat brain support the hypothesis that separate functions are performed by the products of the three SAPK genes.
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PMID:Differential expression of SAPK isoforms in the rat brain. An in situ hybridisation study in the adult rat brain and during post-natal development. 974 3

Recently we showed that human epidermal keratinocytes express the extracellular matrix protein tenascin-C (TN-C) during wound healing, but not in normal adult skin. To gain further insight into the regulation of epidermal TN-C expression, we tested the effect of various stimuli on TN-C expression by cultured keratinocytes. Our results indicate that IL-4 is a very strong inducer of TN-C protein and mRNA expression in normal keratinocytes. Furthermore, TNFalpha and IFNgamma moderately increased TN-C expression. No other cytokines and growth factors that we tested, including various factors that stimulate TN-C expression in mesenchymal cells, significantly affected TN-C secretion by cultured keratinocytes. The regulation of TN-C expression in keratinocytes is distinct from that of fibronectin, since IL-4 and IFNgamma did not affect fibronectin expression in our experiments, and TNFalpha only slightly increased fibronectin levels. To investigate the role of cellular stress response pathways that can be activated by TNFalpha in the regulation of TN-C expression, we tested the effect of different inhibitors and an activator of these intracellular signalling cascades. The results show that the p38 MAP-kinase pathway is not involved in TNFalpha-induced TN-C expression in cultured keratinocytes. Activation of the JNK/SAPK-1 pathway by the addition of sphingomyelinase resulted in a dose-dependent increase of TN-C expression. TN-C expression by squamous carcinoma cell lines was differentially affected by the cytokines that stimulated TN-C expression in normal keratinocytes: TNFalpha again increased TN-C secretion, but IL-4 and IFNgamma had little effect. We conclude that there are distinct regulation mechanisms for TN-C expression in normal keratinocytes, tumor-derived keratinocytes and mesenchymal cells. The observation that TN-C is abundant in inflamed skin is a strong indication that inflammatory cytokines such as IL-4, TNFalpha and IFNgamma could also be involved in the regulation of epidermal TN-C expression in vivo.
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PMID:Tenascin-C expression in human epidermal keratinocytes is regulated by inflammatory cytokines and a stress response pathway. 974 46

We have isolated the human genes encoding the Pyst1 (MKP-3) and Pyst2 (MKP-X) MAP kinase phosphatases. Both genes consist of three exons interrupted by two introns and lack an intron which is conserved in all the other members of this gene family characterised to date. This reinforces the conclusion that Pyst1 and Pyst2 are members of a distinct and structurally homologous subfamily of dual-specificity (Thr/Tyr) MAP kinase phosphatases. We find that Pyst2 mRNA is constitutively expressed in a wide variety of human cell lines including those derived from ovarian, bladder and breast cancers. While there is no evidence for inducible expression of Pyst2 mRNA in human skin fibroblasts in response to cellular stress, Pyst2 mRNA levels are moderately increased in response to serum stimulation. Pyst2 protein is predominantly cytosolic when expressed in COS-1 cells. In common with Pyst1, Pyst2 shows substrate selectivity for the classical p42 (ERK2) isoform of MAP kinase both in vitro and in vivo, displaying much reduced activity towards stress activated MAP kinase isoforms such as JNK-1 and p38/RK. Pyst2 binds p42 MAP kinase in vivo and both MAP kinase binding and substrate selectivity correlate with the ability of different recombinant MAP and SAP kinases to cause catalytic activation of the Pyst2 phosphatase in vitro.
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PMID:Isolation of the human genes encoding the pyst1 and Pyst2 phosphatases: characterisation of Pyst2 as a cytosolic dual-specificity MAP kinase phosphatase and its catalytic activation by both MAP and SAP kinases. 978 80

EMMPRIN (extracellular matrix metalloproteinase inducer) stimulates fibroblast metalloproteinases (MMP) 1, 2 and 3 (Kataoka et al. (1993) Cancer Res. 53, 3154-3158). Here we focus on MMP-1, showing that in lung tumors, MMP-1's cognate mRNA is strongly expressed in stromal fibroblasts adjacent to EMMPRIN-expressing tumor cells. In vitro, EMMPRIN upregulates MMP-1 mRNA expression in a concentration-dependent manner, with a peak accumulation at 24 h. The response is genistein-sensitive, suggesting it is dependent on tyrosine kinase activity. Analysis of tyrosine phosphorylation-dependent MAP kinases ERK 1/2, SAPK/JNK, and p38 showed that the activity of p38 but not that of the other 2 kinases was elevated in response to EMMPRIN. That p38 activity was required for EMMPRIN stimulation of MMP-1 was evident from results showing that the p38 inhibitor SB203580 blocked this response. This is the first available information regarding the mechanism by which tumor-associated molecules upregulate MMP synthesis in stromal fibroblasts.
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PMID:Tumor-derived EMMPRIN (extracellular matrix metalloproteinase inducer) stimulates collagenase transcription through MAPK p38. 987 71


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