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)

Hypertonicity induced by NaCl, but not by urea or mannitol, up-regulates expression of the gamma subunit of Na/K-ATPase in cells of the murine inner medullary collecting duct line (IMCD3) by activation of the Jun kinase 2 (JNK2) pathways. We examined the ionic mediators of the osmosensitive response. An increase in osmolality to 550 milliosmoles per kg of water (mosmol/kgH2O) for 48 h by replacement of NaCl with choline chloride did not prevent the up-regulation of the gamma subunit. Neither Na+ ionophores nor inhibitors of cellular Na+ uptake altered the up-regulation of the gamma subunit or JNK activation. Changes in cell cation concentrations driven by incubation in low-K+ medium were effective in up-regulating the alpha1 subunit of Na/K-ATPase but did not have any effect on the gamma subunit. The replacement of NaCl with choline chloride did not down-regulate gamma-subunit expression in cells adapted to hypertonicity. In contrast, the replacement of NaCl with sodium acetate, or pretreatment of cells with the Cl- channel inhibitor 5-nitro-2-(3-phenylpropyl-amino)benzoic acid (NPPB) completely blocked gamma-subunit up-regulation, inhibited JNK activation, and caused a significant decrement in cell survival in hypertonic but not isotonic conditions. In adapted cells, replacement of 300 mosmol/kgH2O NaCl with sodium acetate resulted in down-regulation of the gamma subunit. In conclusion, we describe a Na+-independent, Cl--dependent mechanism for hypertonicity-mediated activation of the JNK and the subsequent synthesis of the gamma subunit of Na/K-ATPase, which are necessary for cellular survival in these anisotonic conditions.
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PMID:Chloride, not sodium, stimulates expression of the gamma subunit of Na/K-ATPase and activates JNK in response to hypertonicity in mouse IMCD3 cells. 1274 99

We studied the effects of fibroblast growth factor (FGF-10) on alveolar epithelial cell (AEC) Na,K-ATPase regulation. Within 30 min FGF-10 increased Na,K-ATPase activity and alpha1 protein abundance by 2.5-fold at the AEC plasma membrane. Pretreatment of AEC with the mitogen-activated protein kinase (MAPK) inhibitor U0126, a Grb2-SOS inhibitor (SH3-b-p peptide), or a Ras inhibitor (farnesyl transferase inhibitor (FTI 277)), as well as N17-AEC that express a Ras dominant negative protein each prevented FGF-10-mediated Na,K-ATPase recruitment to the AEC plasma membrane. Accordingly, we provide first evidence that FGF-10 upregulates (short-term) the Na,K-ATPase activity in AEC via the Grb2-SOS/Ras/MAPK pathway.
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PMID:Fibroblast growth factor-10 upregulates Na,K-ATPase via the MAPK pathway. 1280 70

Analyses of early molecular and cellular events associated with long-term plasticity remain hampered in Drosophila by the lack of an acute procedure to activate signal transduction pathways, gene expression patterns, and other early cellular events associated with long-term synaptic change. Here we describe the development and first use of such a technique. Bursts of neural activity induced in Drosophila comatosets and CaP60A Kumts mutants, with conditional defects in N-ethylmaleimide-sensitive fusion factor 1 and sarco-endoplasmic reticulum Ca2+ ATPase, respectively, result in persistent (>4 hr) activation of neuronal extracellular signal-regulated kinase (ERK). ERK activation at the larval neuromuscular junction coincides with rapid reduction of synaptic Fasciclin II; in soma, nuclear translocation of activated ERK occurs together with increased transcription of the immediate-early genes Fos and c/EBP (CCAAT element binding protein). The effect of "seizure-stimulation" on ERK activation requires neural activity and is mediated through activation of MEK (MAPK/erk kinase), the MAPKK (mitogen-activated protein kinase kinase) that functions upstream of ERK. Our results (1) provide direct proof for the conservation of synaptic signaling pathways in arthropods, (2) demonstrate the utility of a new genetic tool for analysis of synaptic plasticity in Drosophila, and (3) potentially enable new proteomic and genomic analyses of activity-regulated molecules in an important model organism.
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PMID:Acute induction of conserved synaptic signaling pathways in Drosophila melanogaster. 1286 22

In hypertonicity-stressed (i.e., 600 mOsm) SV40-immortalized rabbit and human corneal epithelial cell layers (RCEC and HCEC, respectively), we characterized the relationship between time-dependent changes in translayer resistance, relative cell volume and modulation of MAPK superfamily activities. Sulforhodamine B permeability initially increased by 1.4- and 2-fold in RCEC and HCEC, respectively. Subsequently, recovery to its isotonic level only occurred in RCEC. Light scattering revealed that in RCEC 1) regulatory volume increase (RVI) extent was 20% greater; 2) RVI half-time was 2.5-fold shorter. However, inhibition of Na-K-2Cl cotransporter and Na/K-ATPase activity suppressed the RVI response more in HCEC. MAPK activity changes were as follows: 1) p38 was wave-like and faster as well as larger in RCEC than in HCEC (90- and 18-fold, respectively); 2) increases in SAPK/JNK activity were negligible in comparison to those of p38; 3) Erk1/2 activity declined to 30-40% of their basal values. SB203580, a specific p38 inhibitor, dose dependently suppressed the RVI responses in both cell lines. However, neither U0126, which inhibits MEK, the kinase upstream of Erk, nor SP600125, inhibitor of SAPK/JNK, had any effect on this response. Taken together, sufficient activation of the p38 limb of the MAPK superfamily during a hypertonic challenge is essential for maintaining epithelial cell volume and translayer resistance. On the other hand, Erk1/2 activity restoration seems to be dependent on cell volume recovery.
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PMID:Hypertonicity-induced p38MAPK activation elicits recovery of corneal epithelial cell volume and layer integrity. 1287 61

Evidence suggests that p38 mitogen-activated protein kinase (MAPK) activation influences cardiac function on an acute basis. The characterization and mechanisms by which this occurs were investigated in the present study. Adult rat ventricular myocytes treated with 1 mM arsenite for 30 min had a 16-fold increase in p38 MAPK phosphorylation that was attenuated by SB-203580 (a p38 MAPK inhibitor). Extracellular signal-regulated protein kinase (ERK) and c-Jun NH2-terminal kinase (JNK) were also minimally activated, but this activation was not sensitive to SB-203580. In addition, arsenite caused a p38 MAPK-independent translocation/activation of protein phosphatase 2a (PP2a) and decrease in phosphorylation of myosin light chain 2 (LC2). Arsenite-p38 MAPK activation led to translocation of heat shock protein 27 but not alpha B-crystallin to the myofilaments. Using isolated cardiomyocytes, we determined that arsenite reduces isometric tension without a change in Ca2+ sensitivity of tension via p38 MAPK and lowers myofibrillar actomyosin Mg2+-ATPase activity in a p38 MAPK-independent manner. Thus arsenite induces a p38 MAPK-independent change in PP2a and LC2 that may account for the arsenite-dependent decrease in ATPase and a p38 MAPK-dependent modification of the myofilaments that decreases myocardial force development.
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PMID:Acute p38 MAPK activation decreases force development in ventricular myocytes. 1288 Dec 12

Interleukin1-beta has been demonstrated previously to reduce the activity and expression of the Na(+)-K(+) pump in the rat jejunum and colon. This work attempts to elucidate the signal transduction pathway underlying its effect using Caco-2 cells. IL-1beta reduced, in these cells also, the activity and expression of ATPase, in a dose and time-dependent manner. The down-regulatory effect of the cytokine on the ATPase was not evident, when p38 MAP kinase was inhibited, but appeared in presence of inhibitors of MEK and NFkappaB, although activation of NF-kappaB was demonstrated by western blot analysis. The effect of IL-1beta on the pump disappeared in the presence of indomethacin, a COX inhibitor. Exogenous PGE2 reduced the expression of the pump within 15 minutes, and this effect was still apparent when p38MAPK was inhibited. Curcumin, a JNK/AP-1 inhibitor, partially abolished the effect of IL-1beta on ATPase expression but did not interfere with the effect of PGE2. These results indicate that IL-1beta reduces the expression of ATPase independently of NFkB but, through a major pathway involving p38 and COX-2/PGE2, and another pathway involving JNK/AP1.
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PMID:Mediators of interleukin-1 beta action Na(+)-K(+)ATPase in Caco-2 cells. 1295 88

We developed an in vivo model for cadmium-induced bone loss in which mice excrete bone mineral in feces beginning 8 h after cadmium gavage. Female mice of three strains [CF1, MTN (metallothionein-wild-type), and MT1,2KO (MT1,2-deficient)] were placed on a low-calcium diet for 2 weeks. Each mouse was gavaged with 200 microg Cd or vehicle only. Fecal calcium was monitored daily for 9 days, beginning 4 days before cadmium gavage, to document the bone response. For CF1 mice, bones were taken from four groups: +/- Cd, 2 h after Cd and +/- Cd, 4 h after Cd. MTN and MT1,2KO strains had two groups each: +/-Cd, 4 h after Cd. PolyA+ RNA preparations from marrow-free shafts of femura and tibiae of each +/- Cd pair were submitted to Incyte Genomics for microarray analysis. Fecal Ca results showed that bone calcium excreted after cadmium differed for the three mouse strains: CF1, 0.24 +/- 0.08 mg; MTN, 0.92 +/- 0.22 mg; and MT1,2KO, 1.7 +/- 0.4 mg. Gene array results showed that nearly all arrayed genes were unaffected by cadmium. However, MT1 and MT2 had Cd+/Cd- expression ratios >1 in all four groups, while all ratios for MT3 were essentially 1, showing specificity. Both probes for MAPK 14 (p38 MAPK) had expression ratios >1, while no other MAPK responded to cadmium. Vacuolar proton pump ATPase and integrin alpha v (osteoclast genes), transferrin receptor, and src-like adaptor protein genes were stimulated by Cd; other src-related genes were unaffected. Genes for bone formation, stress response, growth factors, and signaling molecules showed little or no response to cadmium. Results support the hypothesis that Cd stimulates bone demineralization via a p38 MAPK pathway involving osteoclast activation.
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PMID:Microarray analysis of changes in bone cell gene expression early after cadmium gavage in mice. 1367 60

The important factors that influence the progress of ischemic cardiac lesion are blood flow condition and abnormal cardiac metabolism. Myocardial ischemia is promoted by either an increase in oxygen demand or a shortage of oxygen supply. The Na(+)-Ca(++) ion exchange mechanism is very important for myocardial contraction and cell damage. Na(+)-K(+)ATPase and Ca(++)ATPase are enzyme histochemically localized in subsarcolemmal cisterns, sarcolemmal reticulum and capillary endothelium, and keep myocardial function. These ATPases are impaired by anoxia, superoxides and free radicals. The reduction of O(2) results in the production of superoxides as well as hydrogen peroxide (H(2)O(2)). H(2)O(2) is highly diffusible and induces cell damage. H(2)O(2) appears to affect not only lipids but also intramembranous proteins embedded in the cell membrane. The hydroxyl radical (OH) also participates in lipid hyperoxidation. In the pathogenesis of ischemic and/or reperfused heart disease, ischemia induces rapid or gradual changes in all membrane systems and causes reversible or irreversible injury including necrotic and apoptotic cell death. Advanced glycation end products (AGEs) accumulation induced by diabetic conditioning is an etiologic factor inducing cardiomyopathy. The AGEs protein affects cell changes such as increased number, transformation, functional disturbance and cytokine elimination. In coronary arteries, the migration of smooth muscle cells caused by the taking up of AGEs proteins through the receptor (RAGE), and cytokine discharge are suggested. AGEs accumulation may induce diabetic macroangiopathy through RAGE, and the increase in the level of RAGE expression by endothelial cells could be a reason that diabetes mellitus accelerates atherosclerosis. On the other hand, we also reported that hyperglycemia was a promoting factor of ischemic heart injury in diabetic animals. Ischemic preconditioning is a useful phenomenon that limits myocardial damage. We foused on protein kinase C (PKC), mitogen-activated protein kinase (MAPK) and mitochondrial ATP-dependent potassium (mitoK(ATP)) channel as mediator or end which effector are necessary for adaptation. The opening of the mitoK(ATP) channel induces the depolarization of mitochondria, reducing Ca(++)overload during reperfusion. The regeneration of myocardial cells is confirmed using embryonic stem cells. Myocardial cells that exhibit self-pulsation are generated from mesenchymal stem cells in mesodermal tissues of the bone marrow.
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PMID:Pathogenesis and protection of ischemia and reperfusion injury in myocardium. 1457 38

Renal tubular transport and its regulation are reviewed for Na(+) (and Cl(-)), and for fluid and organic anions (including urate). Filtered Na(+) (and Cl(-)) is reabsorbed along the tubules but only in mammals and birds does most reabsorption occur in the proximal tubules. Reabsorption involves active transport of Na(+) and passive reabsorption of Cl(-). The active Na(+) step always involves Na-K-ATPase at the basolateral membrane, but the entry step at luminal membrane varies among tubule segments and among vertebrate classes (except for Na(+)-2Cl(-)-K(+) cotransporter in diluting segment). Regulation can involve intrinsic, neural and endocrine factors. Proximal tubule fluid reabsorption is dependent on Na(+) reabsorption in all vertebrates studied, except ophidian reptiles. Fluid secretion occurs in glomerular and aglomerular fishes, reptiles and even mammals, but its significance is not always clear. A non-specific transport system for net secretion of organic anions (OAs) exists in the proximal renal tubules of almost all vertebrates. Net transepithelial secretion involves: (1) transport into the cells at the basolateral side against an electrochemical gradient by a tertiary active transport process, in which the final step involves OA/alpha-ketoglutarate exchange and (2) movement out of the cells across the luminal membrane down an electrochemical gradient by unknown carrier-mediated process(es). Regulation may involve protein kinase C and mitogen-activated protein kinase. Urate is net secreted in the proximal tubules of birds and reptiles. This process is urate-specific in reptiles but in birds, it may involve both a urate-specific system and the general OA system.
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PMID:Regulation of renal proximal and distal tubule transport: sodium, chloride and organic anions. 1461 78

This investigation used primary cultured rat vascular smooth muscle cells to examine angiotensin II (Ang II) regulation of Na(+), K(+)-ATPase (Na(+) pump) activity, and Na(+) pump alpha(1)- and beta(1)-subunit gene transcription. This regulation was mediated through both phosphatidylinositol-3 kinase (PI3K) and p42/44 mitogen-activated protein kinase (p42/44(MAPK)) signaling pathways. Both acute (10 min) and prolonged (24 h) treatment with Ang II stimulated Na(+) pump activity. Also, prolonged exposure to Ang II (24 h) increased promoter transcription of the Na(+) pump alpha(1)- and beta(1)-subunits. Furthermore, PI3K activities because well because p42/44(MAPK) phosphorylation were increased within 10 min after Ang II treatment. To determine whether these stimulatory activities of Ang II are acting through Ang II receptors 1 and/or 2 (AT(1), AT(2)), cells were pretreated with either AT(1) receptor blocker losartan or the AT(2) receptor blocker PD 123,319. Indeed, these treatments prevented the stimulatory effect of Ang II on Na(+) pump activity at both acute and 24-h time points. Furthermore, the Ang II-stimulated alpha(1)-subunit promoter transcription was inhibited by losartan but not by the AT(2) receptor blocker. These results indicate that Ang II acts through both the AT(1) and AT(2) receptor to up-regulate Na(+) pump activity; however, Ang II regulates alpha(1)-gene transcription through AT(1) but not AT(2) receptors. It was also observed that the Ang II-stimulated beta(1)-subunit gene transcription is not mediated through either AT(1) or AT(2) receptors. To examine whether the Na(+)/H(+) exchanger is involved in Ang II-stimulated Na(+) pump activity, cells were pretreated with amiloride, a specific inhibitor of the Na(+)/H(+) exchanger. This pretreatment prevented 24 h, but not acute, Ang II-stimulated Na(+) pump activity. The 24-h Ang II-stimulated alpha(1)-subunit promoter transcription was also inhibited by amiloride. This suggests that the prolonged effect of Ang II on Na(+) pump activity is dependent on increased Na(+)/H(+) exchange. Because Ang II treatment for 10 min increased PI3K activity because well because p42/44(MAPK) phosphorylation, studies were performed to determine the involvement of PI3K and p42/44(MAPK) signaling pathways in both Ang II-stimulated Na(+) pump activity and alpha(1)- and beta(1)-gene transcription. Cells were pretreated with either the PI3K inhibitor wortmannin or the p42/44(MAPK) inhibitor PD 98059. Ang II-stimulated PI3K or p42/44(MAPK) activity was inhibited by these pretreatments. Furthermore, pretreatment of cells with the PI3K inhibitors wortmannin and LY29404 or the MAPK inhibitors U0126 and PD 98059 were all observed to inhibit Ang II-stimulated Na(+) pump activity. To more specifically determine the role of PI3K in Ang II-regulation of alpha(1)-and beta(1)-gene transcription, cells were cotransfected with a dominant-negative p85 construct. Cotransfection with dominant-negative p85 reduced Ang II-stimulated alpha(1)-but not beta(1)-gene transcription in vascular smooth muscle cells. These results indicate that Ang II acts through PI3K/p42/44(MAPK) signaling pathways to up-regulate Na(+) pump activity and alpha(1)-gene transcription and that Ang II-regulated beta(1)-gene transcription is not mediated through either PI3K or p42/44 (MAPK) signaling pathways.
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PMID:Angiotensin II regulation of the Na+ pump involves the phosphatidylinositol-3 kinase and p42/44 mitogen-activated protein kinase signaling pathways in vascular smooth muscle cells. 1463 Jul 23


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