SAPKs regulation of ischemic preconditioning

2000 ◽  
Vol 279 (3) ◽  
pp. H901-H907 ◽  
Author(s):  
Motoaki Sato ◽  
Gerald A. Cordis ◽  
Nilanjana Maulik ◽  
Dipak K. Das
Keyword(s):  
Map Kinase ◽  
Map Kinases ◽  
Kinase Inhibitor ◽  
Signal Transduction Pathway ◽  
P38 Map Kinase ◽  
Kinase Activation ◽  
Protein Levels ◽  
Rat Hearts ◽  
Mitogen Activated Protein ◽  
Sb 203580

The role of stress-activated protein kinases (SAPKs), c-Jun NH2-terminal kinase (JNK) and p38 mitogen-activated protein (MAP) kinase, in preconditioning (PC) was examined with the use of isolated rat hearts subjected to four cyclic episodes of 5-min ischemia and 10-min reperfusion followed by 30-min ischemia and 2-h reperfusion (I/R). A group of hearts was preperfused with 100 μM curcumin, a c-Jun and JNK1 inhibitor, or 5 μM SB 203580, a p38 MAP kinase inhibitor. Another group of hearts was preperfused with 20 μM anisomycin, a stimulator for both JNK and p38 MAP kinases. I/R increased the protein levels of JNK1, c-Jun, and p38 MAP kinase. PC also enhanced the induction of these kinases, but subsequent I/R-mediated increase was blocked by PC. Curcumin blocked I/R- and PC-mediated increase in JNK1 and c-Jun protein levels, whereas it had no effects on p38 MAP kinase. SB 203580, on the other hand, was equally effective in reducing the p38 MAP kinase activation but exerted no effects on JNK1 and c-Jun induction. I/R-mediated increased myocardial infarction was reduced by any of the following compounds: anisomycin, curcumin, and SB 203580. The cardioprotective effects of PC were abolished by either curcumin or SB 203580. The results demonstrate that PC is mediated by a signal-transduction pathway involving both JNK1 and p38 MAP kinase. Activation of SAPKs, although transient, is obligatory for PC.

scholarly journals Listeria monocytogenes, an invasive bacterium, stimulates MAP kinase upon attachment to epithelial cells.

1994 ◽  
Vol 5 (4) ◽  
pp. 455-464 ◽  
Author(s):  
P Tang ◽  
I Rosenshine ◽  
B B Finlay
Keyword(s):  
Listeria Monocytogenes ◽  
Epithelial Cells ◽  
Map Kinase ◽  
Tyrosine Phosphorylation ◽  
Map Kinases ◽  
Kinase Inhibitor ◽  
Signal Transduction Pathway ◽  
Host Cells ◽  
Kinase Activation ◽  
Mitogen Activated Protein

Protein tyrosine phosphorylation is an important regulatory mechanism for many cellular processes in eucaryotic cells. During the invasion of the gram-positive pathogen, Listeria monocytogenes, into host epithelial cells, two host proteins become tyrosine phosphorylated. We have identified these major tyrosine phosphorylated species to be two isoforms of mitogen-activated protein (MAP) kinase, the 42 and 44 kDa MAP kinases. This activation begins within 5 to 15 min of bacterial infection. The tyrosine kinase inhibitor, genistein, blocks invasion as well as the tyrosine phosphorylation of these MAP kinases. Using cytochalasin D to block bacterial internalization but not adhesion, we showed that bacterial adherence rather than uptake is required for MAP kinase activation. Internalin mutants, which are unable to adhere efficiently to host cells, do not trigger MAP kinase activation. Other invasive bacteria, including enteropathogenic Escherichia coli (EPEC), and E. coli expressing Yersinia enterocolitica invasion, were not observed to activate MAP kinase during invasion into cultured epithelial cells. These results suggest that L. monocytogenes activates MAP kinase during invasion and a MAP kinase signal transduction pathway may be involved in mediating bacterial uptake.

Ionomycin causes activation of p38 and p42/44 mitogen-activated protein kinases in human neutrophils

2001 ◽  
Vol 281 (1) ◽  
pp. C350-C360 ◽  
Author(s):  
David J. Elzi ◽  
A. Jason Bjornsen ◽  
Todd MacKenzie ◽  
Travis H. Wyman ◽  
Christopher C. Silliman
Keyword(s):  
Map Kinase ◽  
Map Kinases ◽  
P38 Map Kinase ◽  
Polymorphonuclear Neutrophils ◽  
Human Neutrophils ◽  
Kinase Activation ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Activating Transcription Factor

Many receptor-linked agents that prime or activate the NADPH oxidase in polymorphonuclear neutrophils (PMNs) elicit changes in cytosolic Ca2+concentration and activate mitogen-activated protein (MAP) kinases. To investigate the role of Ca2+in the activation of p38 and p42/44 MAP kinases, we examined the effects of the Ca2+-selective ionophore ionomycin on priming and activation of the PMN oxidase. Ionomycin caused a rapid rise in cytosolic Ca2+that was due to both a release of cytosolic Ca2+stores and Ca2+influx. Ionomycin also activated (2 μM) and primed (20–200 nM) the PMN oxidase. Dual phosphorylation of p38 MAP kinase and phosphorylation of its substrate activating transcription factor-2 were detected at ionomycin concentrations that prime or activate the PMN oxidase, while dual phosphorylation of p42/44 MAP kinase and phosphorylation of its substrate Elk-1 were elicited at 0.2–2 μM. SB-203580, a p38 MAP kinase antagonist, inhibited ionomycin-induced activation of the oxidase (68 ± 8%, P < 0.05) and tyrosine phosphorylation of 105- and 72-kDa proteins; conversely, PD-98059, an inhibitor of MAP/extracellular signal-related kinase 1, had no effect. Treatment of PMNs with thapsigargin resulted in priming of the oxidase and activation of p38 MAP kinase. Chelation of cytosolic but not extracellular Ca2+completely inhibited ionomycin activation of p38 MAP kinase, whereas chelation of extracellular Ca2+abrogated activation of p42/44 MAP kinase. These results demonstrate the importance of changes in cytosolic Ca2+for MAP kinase activation in PMNs.

scholarly journals p38 MAP kinase regulates IL-1β responses in cultured airway smooth muscle cells

2000 ◽  
Vol 279 (5) ◽  
pp. L932-L941 ◽  
Author(s):  
Johanne D. Laporte ◽  
Paul E. Moore ◽  
Thomas Lahiri ◽  
Igor N. Schwartzman ◽  
Reynold A. Panettieri ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Map Kinase ◽  
Airway Smooth Muscle ◽  
Signal Transduction Pathway ◽  
P38 Map Kinase ◽  
Airway Smooth Muscle Cells ◽  
P38 Inhibitor ◽  
Mitogen Activated Protein ◽  
Cox 2 ◽  
Sb 203580

We have previously reported that interleukin (IL)-1β causes β-adrenergic hyporesponsiveness in cultured human airway smooth muscle (HASM) cells by increasing cyclooxygenase (COX)-2 expression. The purpose of this study was to determine whether p38 mitogen-activated protein (MAP) kinase is involved in these events. IL-1β (2 ng/ml for 15 min) increased p38 phosphorylation fourfold. The p38 inhibitor SB-203580 (3 μM) decreased IL-1β-induced COX-2 by 70 ± 7% ( P < 0.01). SB-203580 had no effect on PGE2 release in control cells but caused a significant (70–80%) reduction in PGE2 release in IL-1β-treated cells. IL-1β increased the binding of nuclear proteins to the oligonucleotides encoding the consensus sequences for activator protein (AP)-1 and nuclear factor (NF)-κB, but SB-203580 did not affect this binding, suggesting that the mechanism of action of p38 was not through AP-1 or NF-κB activation. The NF-κB inhibitor MG-132 did not alter IL-1β-induced COX-2 expression, indicating that NF-κB activation is not required for IL-1β-induced COX-2 expression in HASM cells. IL-1β attenuated isoproterenol-induced decreases in HASM stiffness as measured by magnetic twisting cytometry, and SB-203580 abolished this effect. These results are consistent with the hypothesis that p38 is involved in the signal transduction pathway through which IL-1β induces COX-2 expression, PGE2 release, and β-adrenergic hyporesponsiveness.

Spontaneous shift in transcriptional profile of explanted glomeruli via activation of the MAP kinase family

2000 ◽  
Vol 279 (5) ◽  
pp. F954-F959 ◽  
Author(s):  
Yoshihisa Ishikawa ◽  
Tsuneo Konta ◽  
Masanori Kitamura
Keyword(s):  
Gene Expression ◽  
Map Kinase ◽  
Map Kinases ◽  
Kinase Inhibitor ◽  
Ex Vivo ◽  
P38 Map Kinase ◽  
Transcriptional Profile ◽  
Activator Protein 1 ◽  
Monocyte Chemoattractant Protein 1 ◽  
Mitogen Activated Protein

To understand how isolation and explantation of glomeruli affect the function of resident cells, the present study investigated the transcriptional profile of explanted normal glomeruli. We found that ex vivo incubation of glomeruli spontaneously expressed monocyte chemoattractant protein-1 (MCP-1) and stromelysin, the genes regulated by activator protein-1 (AP-1). The expression was suppressed by heparin and quercetin, the drugs with anti-AP-1 activities. The gene expression was preceded by 1) induction of AP-1 components c- fos and c- jun and 2) phosphorylation of extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein (MAP) kinase, and c-Jun NH2-terminal kinase (JNK), the upstream inducers/activators of AP-1. Suppression of ERK by PD098059 abrogated induction of c- fos and c- jun, and the p38 MAP kinase inhibitor SB203580 attenuated c- fos expression. Furthermore, treatment with either PD098059, SB203580, or the JNK-AP-1 inhibitor curcumin diminished the expression of MCP-1 and stromelysin. The transcriptional profile of glomerular cells thus alters dramatically after explantation of glomeruli. It is, at least in part, due to activation of multiple MAP kinases that lead to induction of AP-1-dependent gene expression.

p38 MAPK/HSP25 signaling mediates cadmium-induced contraction of mesangial cells and renal glomeruli

2005 ◽  
Vol 288 (6) ◽  
pp. F1133-F1143 ◽  
Author(s):  
Sahoko Hirano ◽  
Xiankui Sun ◽  
Cheryl A. DeGuzman ◽  
Richard F. Ransom ◽  
Kenneth R. McLeish ◽  
...  
Keyword(s):  
Map Kinase ◽  
P38 Mapk ◽  
Map Kinases ◽  
Kinase Inhibitor ◽  
Mesangial Cells ◽  
Smooth Muscle Contraction ◽  
Environmental Pollutant ◽  
P38 Map Kinase ◽  
Dominant Negative ◽  
Kinase Activation

The environmental pollutant cadmium affects human health, with the kidney being a primary target. In addition to proximal tubules, glomeruli and their contractile mesangial cells have also been identified as targets of cadmium nephrotoxicity. Glomerular contraction is thought to contribute to reduced glomerular filtration, a characteristic of cadmium nephrotoxicity. Because p38 MAPK/HSP25 signaling has been implicated in smooth muscle contraction, we examined its role in cadmium-induced contraction of mesangial cells. We report that exposure of mesangial cells to cadmium resulted in 1) cell contraction, 2) activation of MAP kinases, 3) increased HSP25 phosphorylation coincident with p38 MAP kinase activation, 4) sequential phosphorylation of the two phosphorylation sites of mouse HSP25 with Ser15 being phosphorylated before Ser86, 5) reduction of oligomeric size of HSP25, and 6) association of HSP25 with microfilaments. Exposure of isolated rat glomeruli to cadmium also resulted in contraction and increased HSP25 phosphorylation. The cadmium-induced responses were inhibited by the specific p38 MAP kinase inhibitor SB-203580, and cadmium-induced phosphorylation of HSP25 was inhibited by expression of a dominant-negative p38 MAP kinase mutant. These findings tentatively suggest that cadmium-induced nephrotoxicity results, in part, from glomerular contraction due to p38 MAP kinase/HSP25 signaling-dependent contraction of mesangial cells. With regard to the cellular action of HSP25, these data support a change in paradigm: in addition to its well-established cytoprotective function, HSP25 may also be involved in processes that ultimately lead to adverse effects, as is observed in the response of mesangial cells to cadmium.

Hypertonicity activates MAP kinases and inhibits HCO 3 − absorption via distinct pathways in thick ascending limb

1998 ◽  
Vol 275 (4) ◽  
pp. F478-F486 ◽  
Author(s):  
Bruns A. Watts ◽  
John F. Di Mari ◽  
Roger J. Davis ◽  
David W. Good
Keyword(s):  
Map Kinase ◽  
Map Kinases ◽  
Kinase Inhibitor ◽  
Early Response ◽  
P38 Map Kinase ◽  
Renal Tubules ◽  
Thick Ascending Limb ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Erk Activity

Mitogen-activated protein (MAP) kinases are activated by osmotic stress in a variety of cells, but their function and regulation in renal tubules is poorly understood. The present study was designed to examine the osmotic regulation of MAP kinases in the medullary thick ascending limb (MTAL) of the rat and to determine their possible role in the hyperosmotic inhibition of[Formula: see text] absorption in this segment. Tissues from the inner stripe of the outer medulla and microdissected MTALs were incubated at 37°C in control (290 mosmol/kgH2O) or hyperosmotic (300 mM added mannitol) solution for 15 min. Activities of extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38 MAP kinase were then measured using immune complex assays. Hyperosmolality increased p38 MAP kinase activity (2.3-fold) and ERK activity (2.0-fold) but had no effect on JNK activity (1.1-fold). Exposure to hyperosmolality for various times showed that the activation of p38 MAP kinase was rapid (≤5 min) and was sustained for up to 60 min, whereas the activation of ERK was transient (ERK activity peaked at 15 min, then declined to basal levels at 30 min). Pretreatment with the MAP kinase kinase inhibitor PD98059 (15 μM) blocked the hyperosmotic activation of p38 MAP kinase and ERK but did not prevent hyperosmotic inhibition of[Formula: see text] absorption. These results show that hyperosmolality differentially activates p38 MAP kinase and ERK in the MTAL. In contrast, we found no evidence for involvement of JNK in the early response to hyperosmotic stress. Eliminating the activation of p38 MAP kinase and ERK does not prevent hyperosmotic inhibition of [Formula: see text]absorption, suggesting that hyperosmolality inhibits apical membrane Na+/H+exchange (NHE3) activity via a signaling pathway distinct from these MAP kinase pathways.

Evidence for the role of p38 MAP kinase in hypoxia-induced pulmonary vasoconstriction

2002 ◽  
Vol 283 (4) ◽  
pp. L859-L866 ◽  
Author(s):  
M. R. Karamsetty ◽  
J. R. Klinger ◽  
N. S. Hill
Keyword(s):  
Map Kinase ◽  
Map Kinases ◽  
Kinase Inhibitor ◽  
Acute Hypoxia ◽  
Pulmonary Arteries ◽  
P38 Map Kinase ◽  
Pulmonary Vasoconstriction ◽  
Protein Map ◽  
Mitogen Activated Protein

Mitogen-activated protein (MAP) kinases regulate smooth muscle cell contraction. Hypoxia contracts pulmonary arteries by mechanisms that are incompletely understood. We hypothesized that hypoxic contraction of pulmonary arteries involves activation of the MAP kinases. To test this hypothesis, we studied the effects of SB-202190, a p38 MAP kinase inhibitor, PD-98059 and UO-126, two structurally different MEKK inhibitors, and anisomycin, a stimulator of p38 MAP kinase on acute hypoxia-induced contraction in rat conduit pulmonary artery rings precontracted with phenylephrine or KCl. Hypoxia induced a transient contraction, followed by a relaxation, and then a slowly developing sustained contraction. Hypoxia also significantly increased phosphorylation of p38 MAP kinase. SB-202190 did not affect the transient phase but abrogated the sustained phase of hypoxic contraction, whereas anisomycin enhanced both phases of contraction. SB-202190 also attenuated and anisomycin enhanced the phenylephrine-induced contraction. In contrast, PD-98059 and UO-126 had minimal effects on either hypoxic or phenylephrine-induced contraction. None of the treatments modified KCl-induced contraction. We conclude that p38, but not the ERK1/ERK2 MAP kinase pathway, mediates the sustained phase of hypoxic contraction in isolated rat pulmonary arteries.

p38 MAP kinase regulates BMP-4-stimulated VEGF synthesis via p70 S6 kinase in osteoblasts

2003 ◽  
Vol 284 (6) ◽  
pp. E1202-E1209 ◽  
Author(s):  
Haruhiko Tokuda ◽  
Daijiro Hatakeyama ◽  
Toshiyuki Shibata ◽  
Shigeru Akamatsu ◽  
Yutaka Oiso ◽  
...  
Keyword(s):  
Map Kinase ◽  
Map Kinases ◽  
Kinase Inhibitor ◽  
Mammalian Target Of Rapamycin ◽  
Negative Control ◽  
P38 Map Kinase ◽  
S6 Kinase ◽  
P70 S6 Kinase ◽  
Upstream Kinase ◽  
Sb 203580

We previously reported that p70 S6 kinase takes part in bone morphogenetic protein-4 (BMP-4)-stimulated vascular endothelial growth factor (VEGF) synthesis in osteoblast-like MC3T3-E1 cells. Recently, we showed that BMP-4-induced osteocalcin synthesis is regulated by p44/p42 MAP kinase and p38 MAP kinase in these cells. In the present study, we investigated whether the MAP kinases are involved in the BMP-4-stimulated synthesis of VEGF in MC3T3-E1 cells. PD-98059 and U-0126, inhibitors of the upstream kinase of p44/p42 MAP kinase, failed to affect BMP-4-stimulated VEGF synthesis. SB-203580 and PD-169316, inhibitors of p38 MAP kinase, significantly reduced VEGF synthesis, whereas SB-202474, a negative control for p38 MAP kinase inhibitor, had little effect on VEGF synthesis. The BMP-4-stimulated phosphorylation of p38 MAP kinase was not affected by rapamycin, an inhibitor of p70 S6 kinase. On the contrary, SB-203580 and PD-169316 reduced the BMP-4-stimulated phosphorylation of p70 S6 kinase. In addition, anisomycin, an activator of p38 MAP kinase, phosphorylates p70 S6 kinase, and the phosphorylation was suppressed by SB-203580. LY-294002, an inhibitor of phosphatidylinositol 3-kinase, failed to suppress the phosphorylation of p38 MAP kinase induced by BMP-4. Not BMP-4 but anisomycin weakly induced the phosphorylation of phosphoinositide-dependent kinase-1. However, anisomycin had little effect on phosphorylation of either Akt or the mammalian target of rapamycin. Taken together, our results suggest that p38 MAP kinase functions in BMP-4-stimulated VEGF synthesis as a positive regulator at a point upstream from p70 S6 kinase in osteoblasts.

scholarly journals Insulin signal transduction in rat small intestine: role of MAP kinases in expression of mucosal hydrolases

2001 ◽  
Vol 280 (2) ◽  
pp. G229-G240 ◽  
Author(s):  
Soheila Marandi ◽  
Nadine De Keyser ◽  
Alain Saliez ◽  
Anne-Sophie Maernoudt ◽  
Etienne Marc Sokal ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Map Kinase ◽  
Insulin Receptor ◽  
Map Kinases ◽  
Kinase Inhibitor ◽  
Protein Kinase B ◽  
Insulin Signal Transduction ◽  
Mitogen Activated Protein ◽  
Src Homology ◽  
Mucosal Mass

The postreceptor events regulating the signal of insulin downstream in rat intestinal cells have not yet been analyzed. Our objectives were to identify the nature of receptor substrates and phosphorylated proteins involved in the signaling of insulin and to investigate the mechanism(s) by which insulin enhances intestinal hydrolases. In response to insulin, the following proteins were rapidly phosphorylated on tyrosine residues: 1) insulin receptor substrates-1 (IRS-1), -2, and -4; 2) phospholipase C-isoenzyme-γ; 3) the Ras-GTPase-activating protein (GAP) associated with Rho GAP and p62Src; 4) the insulin receptor β-subunit; 5) the p85 subunits of phosphatidylinositol 3-kinase (PI 3-kinase); 6) the Src homology 2 α-collagen protein; 7) protein kinase B; 8) mitogen-activated protein (MAP) kinase-1 and -2; and 9) growth receptor-bound protein-2. Compared with controls, insulin enhanced the intestinal activity of MAP kinase-2 and protein kinase B by two- and fivefold, respectively, but did not enhance p70/S6 ribosomal kinase. Administration of an antireceptor antibody or MAP-kinase inhibitor PD-98059 but not a PI 3-kinase inhibitor (wortmannin) to sucklings inhibited the effects of insulin on mucosal mass and enzyme expression. We conclude that normal rat enterocytes express all of the receptor substrates and mediators involved in different insulin signaling pathways and that receptor binding initiates a signal enhancing brush-border membrane hydrolase, which appears to be regulated by the cascade of MAP kinases but not by PI 3-kinase.

scholarly journals Novel members of the mitogen-activated protein kinase activator family in Xenopus laevis

1993 ◽  
Vol 13 (9) ◽  
pp. 5738-5748
Author(s):  
B M Yashar ◽  
C Kelley ◽  
K Yee ◽  
B Errede ◽  
L I Zon
Keyword(s):  
Protein Kinase ◽  
Xenopus Laevis ◽  
Map Kinase ◽  
Protein Kinases ◽  
Map Kinases ◽  
Yeast Cells ◽  
Amino Acid Sequence Similarity ◽  
Kinase Activation ◽  
Mitogen Activated Protein ◽  
Activation Pathways

Mitogen-activated protein (MAP) kinases comprise an evolutionarily conserved family of proteins that includes at least three vertebrate protein kinases (p42, p44, and p55 MAPK) and five yeast protein kinases (SPK1, MPK1, HOG1, FUS3, and KSS1). Members of this family are activated by a variety of extracellular agents that influence cellular proliferation and differentiation. In Saccharomyces cerevisiae, there are multiple physiologically distinct MAP kinase activation pathways composed of structurally related kinases. The recently cloned vertebrate MAP kinase activators are structurally related to MAP kinase activators in these yeast pathways. These similarities suggest that homologous kinase cascades are utilized for signal transduction in many, if not all, eukaryotes. We have identified additional members of the MAP kinase activator family in Xenopus laevis by a polymerase chain reaction-based analysis of embryonic cDNAs. One of the clones identified (XMEK2) encodes a unique predicted protein kinase that is similar to the previously reported activator (MAPKK) in X. laevis. XMEK2, a highly expressed maternal mRNA, is developmentally regulated during embryogenesis and expressed in brain and muscle. Expression of XMEK2 in yeast cells suppressed the growth defect associated with loss of the yeast MAP kinase activator homologs, MKK1 and MKK2. Partial sequence of a second cDNA clone (XMEK3) identified yet another potential MAP kinase activator. The pattern of expression of XMEK3 is distinct from that of p42 MAPK and XMEK2. The high degree of amino acid sequence similarity of XMEK2, XMEK3, and MAPKK suggests that these three are related members of an amphibian family of protein kinases involved in the activation of MAP kinase. Discovery of this family suggests that multiple MAP kinase activation pathways similar to those in yeast cells exist in vertebrates.

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