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)

Endothelial cell injury underlies an increased occurrence of thromboembolic vascular disease in hereditary hyperhomocysteinemia. We have previously shown that homocysteine causes activation of c-Jun NH(2)-terminal kinase (JNK) and activating transcription factor 3/liver regenerating factor 1 (ATF3/LRF1) and induces apoptosis in human umbilical vein endothelial cells (HUVECs). In this study, the activation of JNK and ATF3 in HUVECs was mediated by the endoplasmic reticulum (ER) resident transmembrane kinase IRE1alpha and beta, which sense and transduce signal of the accumulationj of unfolded proteins in the ER. Moreover, dominant negative mutants of tumor necrosis factor receptor-associated factor 2 and mitogen-activated kinase kinase 4 and 7, as well as antisense ATF3 cDNA, inhibited cell death by homocysteine. These results indicate that the activation of JNK and ATF3 through the ER stress of homocysteine plays a role in the homocysteine-induced cell death. The JNK-ATF3 pathway may be implicated in endothelial cell injury associated with hereditary hyperhomocysteinemia.
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PMID:Activation of JNK and transcriptional repressor ATF3/LRF1 through the IRE1/TRAF2 pathway is implicated in human vascular endothelial cell death by homocysteine. 1172 7

The mitogen-activated kinases are structurally related proline-directed serine/threonine kinases that phosphorylate similar phosphoacceptor sites and yet, in vivo, they exhibit stringent substrate specificity. Specific targeting domains (kinase docking domains) facilitate kinase-substrate interaction and play a major role in substrate specificity determination. The c-Jun N-terminal kinase (JNK) consensus docking domain comprises of a KXXK/RXXXXLXL motif located in the delta-domain of the c-Jun N-terminal to the phosphoacceptor site. The c-Jun dimerization protein 2 is phosphorylated by JNK on Thr-148. Activating transcription factor 3 (ATF3) is a basic leucine zipper protein which is highly homologous to c-Jun dimerization protein 2 (JDP2), especially within the threonine/proline phosphoacceptor site, Thr-148. Nevertheless, ATF3 does not serve as a JNK substrate in vitro or in vivo. Using ATF3 and JDP2 protein chimaeras, we mapped the JNK-docking domain within JDP2. Although a JNK consensus putative docking site is located within the JDP2 leucine zipper motif, this domain does not function to recruit JNK to JDP2. A novel putative docking domain located C-terminally to the JDP2 phosphoacceptor site was identified. This domain, when fused to the ATF3 heterologous phosphoacceptor site, can direct its phosphorylation by JNK. In addition, although the novel JNK-docking domain was found to be necessary for p38 phosphorylation of JDP2 on Thr-148, it was not sufficient to confer JDP2 phosphorylation by the p38 kinase.
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PMID:Differential targeting of the stress mitogen-activated protein kinases to the c-Jun dimerization protein 2. 1222 89

ATF3 (Activating transcription factor 3), a member of the CREB/ATF family, can be induced by stress and growth factors in mammalian cells, and is thought to play an important role in the cardiovascular system. However, little is currently known about how the induction of ATF3 is regulated, except that the JNK pathway is involved. Here, we investigated the differential roles of the MAPK pathways involved in TNFalpha (tumour necrosis factor alpha)-induced ATF3 expression in vascular endothelial cells. In human umbilical vein endothelial cells, the expression of constitutively active MKK7 (MAPK kinase 7) increased the number of ATF3-positive cells, and dominant negative MKK7 suppressed the TNFalpha-induced expression of ATF3, indicating a requirement for the JNK pathway. In contrast, the expression of constitutively active or dominant negative MEK1/2 (MAPK/ERK kinase 1/2) suppressed or enhanced TNFalpha-mediated induction of ATF3, respectively. In support of this, the MEK1/2 specific inhibitor U0126 enhanced the expression of ATF3 induced by TNFalpha. Furthermore, the ERK pathway inhibits the TNFalpha-mediated induction of ATF3 mRNA, but not its stability, suggesting the involvement of ERK activity in the transcriptional regulation of the ATF3 gene. Our results suggest that TNFalpha-induced ATF3 gene expression is bidirectionally regulated by the JNK and ERK pathways in vascular endothelial cells.
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PMID:TNFalpha-induced ATF3 expression is bidirectionally regulated by the JNK and ERK pathways in vascular endothelial cells. 1472 8

Activating transcription factor 3 (ATF3) is a stress-inducible gene and encodes a member of the ATF/CREB family of transcription factors. However, the physiological significance of ATF3 induction by stress signals is not clear. In this report, we describe several lines of evidence supporting a role of ATF3 in stress-induced beta-cell apoptosis. First, ATF3 is induced in beta cells by signals relevant to beta-cell destruction: proinflammatory cytokines, nitric oxide, and high concentrations of glucose and palmitate. Second, induction of ATF3 is mediated in part by the NF-kappaB and Jun N-terminal kinase/stress-activated protein kinase signaling pathways, two stress-induced pathways implicated in both type 1 and type 2 diabetes. Third, transgenic mice expressing ATF3 in beta cells develop abnormal islets and defects secondary to beta-cell deficiency. Fourth, ATF3 knockout islets are partially protected from cytokine- or nitric oxide-induced apoptosis. Fifth, ATF3 is expressed in the islets of patients with type 1 or type 2 diabetes, and in the islets of nonobese diabetic mice that have developed insulitis or diabetes. Taken together, our results suggest ATF3 to be a novel regulator of stress-induced beta-cell apoptosis.
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PMID:Role for activating transcription factor 3 in stress-induced beta-cell apoptosis. 1519 29

Several agonists acting on G protein-coupled receptors (GPCR) enhance the mitogenic effect of epidermal growth factor (EGF) in rat hepatocytes, through mechanisms that have only partially been clarified. Results in various cells have led to the idea that a major mechanism for GPCR-mediated stimulation of cell growth is transactivation of receptor tyrosine kinases, particularly the EGF receptor (EGFR), leading to rapid phosphorylation of the EGFR and activation of downstream signaling pathways. In the present study cultured rat hepatocytes were exposed to various GPCR agonists, including vasopressin, angiotensin II (Ang.II), norepinephrine, or prostaglandin F(2 alpha) (PGF(2 alpha)). None of these agents increased the phosphorylation of the EGFR or the docking protein Shc. Furthermore, we examined the effect of the GPCR agonists on the expression of two early response genes believed to be involved in growth activation. The GPCR agonists increased the mRNA expression of c-myc, and also of activating transcription factor 3 (ATF3)/liver regeneration factor-1 (LRF-1), which is a novel finding. Finally, the selective EGFR inhibitor AG1478 did not suppress the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) or the induction of c-myc or ATF3/LRF-1 by the GPCR agonists, and did not prevent the comitogenic effects induced by these agents, while it blocked the effect of EGF on these responses. The results suggest that GPCR agonists induce expression of ATF3/LRF-1 and c-myc and exert comitogenic effects through mechanisms that do not require EGFR transactivation.
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PMID:G protein-coupled receptor agonist-stimulated expression of ATF3/LRF-1 and c-myc and comitogenic effects in hepatocytes do not require EGF receptor transactivation. 1538 57

To investigate whether activation of mitogen-activated protein kinase (MAPK) in damaged and/or undamaged primary afferents participates in neuropathic pain after partial nerve injury, we examined the phosphorylation of extracellular signal-regulated protein kinase (ERK), p38 MAPK, and c-Jun N-terminal kinase (JNK) in the L4 and L5 dorsal root ganglion (DRG) in the L5 spinal nerve ligation (SNL) model. We first confirmed, using activating transcription factor 3 and neuropeptide Y immunoreactivity, that virtually all L4 DRG neurons are spared from axotomy in this model. In the injured L5 DRG, the L5 SNL induced the activation of ERK, p38, and JNK in different populations of DRG neurons. In contrast, in the uninjured L4 DRG, the L5 SNL induced only p38 activation in tyrosine kinase A-expressing small- to medium-diameter neurons. Intrathecal ERK, p38, and JNK inhibitor infusions reversed SNL-induced mechanical allodynia, whereas only p38 inhibitor application attenuated SNL-induced thermal hyperalgesia. Furthermore, the L5 dorsal rhizotomy did not prevent SNL-induced thermal hyperalgesia. We therefore hypothesized that p38 activation in the uninjured L4 DRG might be involved in the development of heat hypersensitivity in the L5 SNL model. In fact, the treatment of the p38 inhibitor and also anti-nerve growth factor reduced SNL-induced upregulation of brain-derived neurotrophic factor and transient receptor potential vanilloid type 1 expression in the L4 DRG. Together, our results demonstrate that the L5 SNL induces differential activation of MAPK in injured and uninjured DRG neurons and, furthermore, that MAPK activation in the primary afferents may participate in generating pain hypersensitivity after partial nerve injury.
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PMID:Role of mitogen-activated protein kinase activation in injured and intact primary afferent neurons for mechanical and heat hypersensitivity after spinal nerve ligation. 1553 93

In the present work, insulin's regulation of expression of activating transcription factor 3 (ATF-3), the putative transcription factor proline-rich induced protein (Pip)92, and insulin-inducible gene-1 (Insig-1) (an ER resident protein involved in regulation of sterol-responsive element-binding protein 1 activation) have been examined in a liver-derived cell line (rat H4IIE hepatoma cells). We report that: 1) insulin-induced transcription of ATF-3, Pip92, and Insig-1 required MEK-ERK activation; 2) insulin-induced transcription of ATF-3 and Pip92 reached maximum levels within 15 min and was blocked by wortmannin but not LY294002; 3) in contrast, the maximum level of insulin-induced transcription of Insig-1 was delayed and was not blocked by either wortmannin or LY294002; 4) insulin activated ERK1/2 in two distinct phases, a rapid peak and a later plateau; 5) the delayed plateau phase of insulin-induced ERK1/2 activation was partially phosphatidylinositol 3-OH-kinase dependent; and 6) however, the rapid, insulin-induced peak of ERK1/2 activation was blocked by wortmannin but not LY294002.
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PMID:Blockade of rapid versus prolonged extracellularly regulated kinase 1/2 activation has differential effects on insulin-induced gene expression. 1573 59

Oxidative stress is a key player in a variety of neurodegenerative disorders including Parkinson's disease. Widely used as a parkinsonian mimetic, 6-hydroxydopamine (6-OHDA) generates reactive oxygen species (ROS) as well as coordinated changes in gene transcription associated with the unfolded protein response (UPR) and apoptosis. Whether 6-OHDA-induced UPR activation is dependent on ROS has not yet been determined. The present study used molecular indicators of oxidative stress to place 6-OHDA-generated ROS upstream of the appearance of UPR markers such as activating transcription factor 3 (ATF3) and phosphorylated stress-activated protein kinase (SAPK/JNK) signaling molecules. Antioxidants completely blocked 6-OHDA-mediated UPR activation and rescued cells from toxicity. Moreover, cytochrome c release from mitochondria was observed after the appearance of early UPR markers, suggesting that cellular stress pathways are responsible for its release. Mechanistically, the 6-OHDA-induced UPR was independent of intracellular calcium changes. Rather, evidence of protein oxidation was observed before the expression of UPR markers, suggesting that the rapid accumulation of damaged proteins triggered cell stress/UPR. Taken together, 6-OHDA-mediated cell death in dopaminergic cells proceeds via ROS-dependent UPR up-regulation which leads to an interaction with the intrinsic mitochondrial pathway and downstream caspase activation.
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PMID:Oxidative stress-triggered unfolded protein response is upstream of intrinsic cell death evoked by parkinsonian mimetics. 1698 35

ATF3 (activating transcription factor 3) gene encodes a member of the ATF/CREB (cAMP-response-element-binding protein) family of transcription factors. Its expression is induced by a wide range of signals, including stress signals and signals that promote cell proliferation and motility. Thus the ATF3 gene can be characterized as an 'adaptive response' gene for the cells to cope with extra- and/or intra-cellular changes. In the present study, we demonstrate that the p38 signalling pathway is involved in the induction of ATF3 by stress signals. Ectopic expression of CA (constitutively active) MKK6 [MAPK (mitogen-activated protein kinase) kinase 6], a kinase upstream of p38, indicated that activation of the p38 pathway is sufficient to induce the expression of the ATF3 gene. Inhibition of the pathway indicated that the p38 pathway is necessary for various signals to induce ATF3, including anisomycin, IL-1beta (interleukin 1beta), TNFalpha (tumour necrosis factor alpha) and H2O2. Analysis of the endogenous ATF3 gene indicates that the regulation is at least in part at the transcription level. Specifically, CREB, a transcription factor known to be phosphorylated by p38, plays a role in this induction. Interestingly, the ERK (extracellular-signal-regulated kinase) and JNK (c-Jun N-terminal kinase)/SAPK (stress-activated protein kinase) signalling pathways are neither necessary nor sufficient to induce ATF3 in the anisomycin stress paradigm. Furthermore, analysis of caspase 3 activation indicated that knocking down ATF3 reduced the ability of MKK6(CA) to exert its pro-apoptotic effect. Taken together, our results indicate that a major signalling pathway, the p38 pathway, plays a critical role in the induction of ATF3 by stress signals, and that ATF3 is functionally important to mediate the pro-apoptotic effects of p38.
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PMID:The regulation of ATF3 gene expression by mitogen-activated protein kinases. 1701 22

Cerebellar granule neurons (CGNs) depend on potassium depolarization for survival and undergo apoptosis when deprived of depolarizing concentration of potassium. Activating transcription factor 3 (ATF3), a stress-inducible protein, belongs to the ATF/CREB family of transcription factors family and is involved in cell growth and apoptosis. However, the role of ATF3 in neuronal apoptosis remains unknown. Here, we showed that ATF3 was up-regulated under potassium deprivation in CGNs, and this induction was preceded by a rapid and sustained activation of c-Jun NH(2)-terminal kinase/c-Jun signaling pathway, which plays a fundamental role in neuronal apoptosis. Furthermore, ATF3 up-regulation was abolished by inhibition of JNK or knockdown of c-Jun. Finally, knockdown of ATF3 by RNA interference protected CGNs from potassium deprivation-induced apoptosis. Taken together, our results indicate that ATF3 is a downstream target of JNK/c-Jun pathway and contributes to apoptosis induced by potassium deprivation in rat CGNs.
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PMID:Activating transcription factor 3 up-regulated by c-Jun NH(2)-terminal kinase/c-Jun contributes to apoptosis induced by potassium deprivation in cerebellar granule neurons. 1817 18


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