Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Big MAP kinase 1 (BMK1/ERK5) plays a critical role in pre-natal development of the cardiovascular system and post-natal eccentric hypertrophy of the heart. Of the two isoforms upstream of MAPK-kinase 5 (MEK5) known to exist, only the longer MEK5alpha isoform potently activates BMK1. We generated cardiac-specific constitutively active form of the MEK5alpha (CA-MEK5alpha transgenic (Tg) mice), and observed a 3 to 4-fold increase in endogenous BMK1 activation and hyperphosphorylation of connexin 43 in the ventricles of the Tg compared to wild-type mice. The CA-MEK5alpha-Tg-mice demonstrated a profoundly accelerated recovery of left ventricular developed pressure after ischemia/reperfusion. We propose a novel role for BMK1 in protecting the heart from ischemia/reperfusion-induced cardiac injury.
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PMID:Activation of big MAP kinase 1 (BMK1/ERK5) inhibits cardiac injury after myocardial ischemia and reperfusion. 1514 5

Endothelial dysfunction (ED) is an early event in atherosclerotic disease, preceding clinical manifestations and complications. Increased reactive oxygen species (ROS) have been implicated as important mechanisms that contribute to ED, and ROS's may function as intracellular messengers that modulate signaling pathways. Several intracellular signal events stimulated by ROS have been defined, including the identification of two members of the mitogen activated protein kinase family (ERK1/2 and big MAP kinase, BMK1), tyrosine kinases (Src and Syk) and different isoenzymes of PKC as redox-sensitive kinases. ROS regulation of signal transduction components include the modification in the activity of transcriptional factors such as NFkB and others that result in changes in gene expression and modifications in cellular responses. In order to understand the intracellular mechanisms induced by ROS in endothelial cells (EC), we are studying the response of human umbilical cord vein endothelial cells to increased ROS generation by different pro-atherogenic stimuli. Our results show that Homocysteine (Hcy) and oxidized LDL (oxLDL) enhance the activity and expression of oxidative stress markers, such as NFkB and heme oxygenase 1. These results suggest that these pro-atherogenic stimuli increase oxidative stress in EC, and thus explain the loss of endothelial function associated with the atherogenic process.
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PMID:Endothelial cell oxidative stress and signal transduction. 1569 75

Big MAP kinase 1 (BMK1 or ERK5) is a key mediator of endothelial cell (EC) function as shown by impaired embryonic angiogenesis and vascular collapse in BMK1 knockout mice. Hypoxia inducible factor 1alpha (HIF1alpha), a potent mediator of angiogenesis, is positively regulated by the MAP kinases, ERK1/2. Because BMK1 deficiency is associated with impaired angiogenesis we hypothesized that BMK1 might regulate HIF1alpha. To test this hypothesis, bovine lung microvascular ECs (BLMECs) were transfected with HIF1alpha and BMK1 cDNAs, and stimulated by hypoxia. HIF1alpha activity was measured by a reporter gene assay in which luciferase expression was driven by HIF1alpha activation. Hypoxia (1% O2, 24 hours) stimulated HIF1alpha activity by 5.1+/-0.6 fold. In the presence of dominant negative (DN)-BMK1, which inhibited BMK1 activity, hypoxia induced HIF1alpha activity was enhanced significantly to 6.4+/-0.4 fold. BMK1 activation by constitutively active (CA)-MEK5 inhibited HIF1alpha activity by 46+/-4%, suggesting BMK1 functions as a negative regulator of HIF1alpha activation. Activation of BMK1 reduced HIF1alpha protein levels. Ubiquitination inhibitors (30 micromol/L ALLN, 2 micromol/L lactacystin, or 100 nmol/L MG132) reduced the BMK1-mediated effect on HIF1alpha expression by >80%, suggesting that BMK1 stimulated HIF1alpha proteolysis. The negative effect of BMK1 on HIF1alpha was functionally important because transfection with CA-MEK5 significantly decreased EC migration by 68+/-10%, and inhibited angiogenesis (in vitro Matrigel assay) by 76+/-7%. In summary, BMK1 is a novel negative regulator of HIF1alpha and angiogenesis by increasing HIF1alpha ubiquitination and inhibiting HIF1alpha activity in endothelial cells.
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PMID:BMK1/ERK5 is a novel regulator of angiogenesis by destabilizing hypoxia inducible factor 1alpha. 1587 8

We have analyzed the sma-5(n678) mutant in C. elegans to elucidate mechanisms controlling body size. The sma-5 mutant is very small, grows slowly and its intestinal granules look abnormal. We found a 15 kb deletion in the mutant that includes a 226 bp deletion of the 3' end of the W06B3.2-coding sequence. Based on this result, rescue experiments, RNAi experiments and a newly isolated deletion mutant of W06B3.2, we conclude that W06B3.2 is the sma-5 gene. The sma-5 mutant has much smaller intestine, body wall muscles and hypodermis than those of the wild type. However, the number of intestinal cells or body wall muscle cells is not changed, indicating that the sma-5 mutant has much smaller cells. In relation to the smaller cell size, the amount of total protein is drastically decreased; however, the DNA content of the intestinal nuclei is unchanged in the sma-5 mutant. The sma-5 gene is expressed in intestine, excretory cell and hypodermis, and encodes homologs of a mammalian MAP kinase BMK1/ERK5/MAPK7, which was reported to control cell cycle and cell proliferation. Expression of the sma-5 gene in hypodermis is important for body size control, and it can function both organ-autonomously and non-autonomously. We propose that the sma-5 gene functions in a MAP kinase pathway to regulate body size mainly through control of cell growth.
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PMID:Control of body size by SMA-5, a homolog of MAP kinase BMK1/ERK5, in C. elegans. 1594 83

Despite nearly twenty years of research into the field of ischemic preconditioning, the actual mechanism of protection remains unclear. However, much progress has been made in elucidating the signal transduction pathways that convey the extracellular signal initiated by the preconditioning stimulus to the intracellular targets of cardioprotection, with many of these pathways involving the activation of a diverse array of survival protein kinase cascades. The powerful protective benefits of ischemic preconditioning have not yet been realised in the clinical arena, not least because of the prerequisite for any preconditioning intervention to be applied prior to the onset of index ischemia, which in the case of an acute myocardial infarction is difficult to institute. In this regard, the newly described phenomenon of ischemic postconditioning, which comprises a cardioprotective intervention that can be applied at the time of myocardial reperfusion, offers a far more attractive and amenable approach to myocardial protection. Interestingly, certain survival protein kinase cascades recruited at the time of myocardial reperfusion appear to be shared by both ischemic preconditioning and postconditioning, thereby offering a potentially common target of cardioprotection. The often disputed roles these different protein kinases play in mediating the cardioprotective effects of ischemic preconditioning and postconditioning are reviewed in this article, and include protein kinases C, G, and A, members of the MAPK family (Erk1/2, p38, JNK and BMK1), the PI3K-Akt cascade, and the JAK-STAT pathway.
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PMID:Survival kinases in ischemic preconditioning and postconditioning. 1654 52

We isolated and characterized BMK1, a gene encoding a mitogen-activated protein kinase (MAPK), from the rice leaf spot pathogen Bipolaris oryzae. The deduced amino acid sequence showed significant homology with Fus3/Kss1 MAPK homologues from other phytopathogenic fungi. The BMK1 disruptants showed impaired hyphal growth, no conidial production, and loss of virulence against rice leaves, indicating that the BMK1 is essential for conidiation and pathogenicity in B. oryzae.
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PMID:A MAP kinase gene, BMK1, is required for conidiation and pathogenicity in the rice leaf spot pathogen Bipolaris oryzae. 1654 58

An abundance of scientific literature exists demonstrating that oxidative stress influences the MAPK signaling pathways. This review summarizes these findings for the ERK, JNK, p38, and BMK1 pathways. For each of these different MAPK signaling pathways, the following is reviewed: the proteins involved in the signaling pathways, how oxidative stress can activate cellular signaling via these pathways, the types of oxidative stress that are known to induce activation of the different pathways, and the specific cell types in which oxidants induce MAPK responses. In addition, the functional outcome of oxidative stress-induced activation of these pathways is discussed. The purpose of this review is to provide the reader with an overall understanding and appreciation of oxidative stress-induced MAPK signaling.
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PMID:Reactive oxygen species-induced activation of the MAP kinase signaling pathways. 1698 31

Cell integrity MAPK (mitogen-activated protein kinase) function can be provided in yeast cells by either the native Slt2(Mpk1)p of yeast or by a heterologously expressed human ERK5 (extracellular-signal-regulated kinase 5). Both of these MAPKs need the Hsp90 (heat-shock protein 90) chaperone for their activation, so that when Hsp90 function is compromised their activities are low. This, in turn, affects the capacity of these MAPKs to control the transcription factors that regulate cell integrity genes.
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PMID:Hsp90 chaperone control over transcriptional regulation by the yeast Slt2(Mpk1)p and human ERK5 mitogen-activated protein kinases (MAPKs). 1705 97

Human endothelial nitric oxide synthase (eNOS) plays a crucial role in maintaining blood pressure homeostasis and vascular integrity. eNOS gene expression may be upregulated by a signaling pathway, including PI-3Kgamma--> Jak2--> MEK1 --> ERK1/2--> PP2A. It remains unclear whether other mitogen-activated protein kinase (MAPK) family members, such as JNK, p38 kinase, and ERK5/BMK1, also modulate eNOS gene expression. Our purpose, therefore, is to shed light on the effect of the p38 MAPK signaling pathway on the regulation of eNOS promoter activity. The results showed that a red fluorescent protein reporter gene vector containing the full length of the human eNOS promoter was first successfully constructed, expressing efficiently in ECV304 cells with the characteristics of real time observation. The wild-types of p38alpha, p38beta, p38gamma, and p38delta signal molecules all markedly downregulated promoter activity, which could be reversed by their negative mutants, including p38alpha (AF), p38beta (AF), p38gamma (AF), and p38delta (AF). Promoter activity was also significantly downregulated by MKK6b (E), an active mutant of an upstream kinase of p38 MAPK. The reduction in promoter activity by p38 MAPK could be blocked by treatment with a p38 MAPK specific inhibitor, SB203580. Moreover, the activation of endogenous p38 MAPK induced by lipopolysaccharide resulted in a prominent reduction in promoter activity. These findings strongly suggest that the activation of the p38 MAPK signaling pathway may be implicated in the downregulation of human eNOS promoter activity.
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PMID:Downregulation of human endothelial nitric oxide synthase promoter activity by p38 mitogen-activated protein kinase activation. 1716 42

Astrocytes, the major glia in the nonmyelinated optic nerve head (ONH), connect via gap junctions built of connexin-43 (Cx43) to form a functional syncytium allowing communication and control of ionic and metabolic homeostasis of retinal ganglion cells (RGCs) axon. We examined gap junction intercellular communication (GJIC) by scrape loading assays in human ONH astrocytes exposed to hydrostatic (HP) or ambient pressure (CP) in vitro. Immunostaining, immunoprecipitation, and immunoblots were used to detect Cx43 distribution and phosphorylation in astrocytes exposed to HP with/without EGF receptor (EGFR) tyrosine kinase inhibitors AG1478 and AG82 and MAPK inhibitors U0126, PD98059, and SB203580. The data indicates that upon exposure to HP, astrocytes decrease GJIC and exhibit altered cellular localization and phosphorylation of Cx43. Inhibition of EGFR blocked the effects of HP on GJIC and HP-induced Cx43 tyrosine phosphorylation. Inhibitors of MAPK- ERK1/2 and -p38 caused partial closure of GJIC under CP and HP, which was maintained for 6 h. Inhibition of Big Mitogen-Activated Kinase 1/ERK5 (BMK1/ERK5) caused partial closure under CP and HP followed by full recovery after 6 h. Inhibition of MAPK did not affect the HP-induced increase in Cx43 serine 279/282 phosphorylation. We conclude that activation of the EGFR pathway in response to HP leads to decrease of GJIC via tyrosine phosphorylation of Cx43 in ONH astrocytes. In glaucoma under conditions of elevated intraocular pressure (IOP), astrocytes may lose GJIC altering the homeostasis of RGC axons, adopting the reactive phenotype, contributing to glaucomatous neuropathy.
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PMID:Pressure induces loss of gap junction communication and redistribution of connexin 43 in astrocytes. 1755 25


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