Acute p38 MAPK activation decreases force development in ventricular myocytes

2003 ◽  
Vol 285 (6) ◽  
pp. H2578-H2586 ◽  
Author(s):  
Yi Chen ◽  
Ravi Rajashree ◽  
Qinghang Liu ◽  
Polly Hofmann
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Ventricular Myocytes ◽  
Fold Increase ◽  
Isometric Tension ◽  
Mitogen Activated Protein Kinase ◽  
Independent Manner ◽  
Mapk Activation ◽  
Force Development ◽  
Sb 203580

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 αB-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.

scholarly journals APPL1 mediates adiponectin-stimulated p38 MAPK activation by scaffolding the TAK1-MKK3-p38 MAPK pathway

2011 ◽  
Vol 300 (1) ◽  
pp. E103-E110 ◽  
Author(s):  
Xiaoban Xin ◽  
Lijun Zhou ◽  
Caleb M. Reyes ◽  
Feng Liu ◽  
Lily Q. Dong
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
Adaptor Protein ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Scaffolding Protein ◽  
Mapk Activation ◽  
P38 Mapk Pathway ◽  
Mitogen Activated Protein

The adaptor protein APPL1 mediates the stimulatory effect of adiponectin on p38 mitogen-activated protein kinase (MAPK) signaling, yet the underlying mechanism remains unclear. Here we show that, in C2C12 cells, overexpression or suppression of APPL1 enhanced or suppressed, respectively, adiponectin-stimulated p38 MAPK upstream kinase cascade, consisting of transforming growth factor-β-activated kinase 1 (TAK1) and mitogen-activated protein kinase kinase 3 (MKK3). In vitro affinity binding and coimmunoprecipitation experiments revealed that TAK1 and MKK3 bind to different regions of APPL1, suggesting that APPL1 functions as a scaffolding protein to facilitate adiponectin-stimulated p38 MAPK activation. Interestingly, suppressing APPL1 had no effect on TNFα-stimulated p38 MAPK phosphorylation in C2C12 myotubes, indicating that the stimulatory effect of APPL1 on p38 MAPK activation is selective. Taken together, our study demonstrated that the TAK1-MKK3 cascade mediates adiponectin signaling and uncovers a scaffolding role of APPL1 in regulating the TAK1-MKK3-p38 MAPK pathway, specifically in response to adiponectin stimulation.

p38 mitogen-activated protein kinase inhibits calcium-dependent chloride secretion in T84 colonic epithelial cells

2003 ◽  
Vol 284 (2) ◽  
pp. C339-C348 ◽  
Author(s):  
Stephen J. Keely ◽  
Kim E. Barrett
Keyword(s):  
Protein Kinase ◽  
Epithelial Cells ◽  
Signaling Pathway ◽  
P38 Mapk ◽  
Mitogen Activated Protein Kinase ◽  
Muscarinic Agonist ◽  
Colonic Epithelial Cells ◽  
Mitogen Activated Protein ◽  
Intracellular Ca ◽  
Sb 203580

We have previously shown that Ca2+-dependent Cl−secretion across intestinal epithelial cells is limited by a signaling pathway involving transactivation of the epidermal growth factor receptor (EGFR) and activation of ERK mitogen-activated protein kinase (MAPK). Here, we have investigated a possible role for p38 MAPK in regulation of Ca2+-dependent Cl− secretion. Western blot analysis of T84 colonic epithelial cells revealed that the muscarinic agonist carbachol (CCh; 100 μM) stimulated phosphorylation and activation of p38 MAPK. The p38 inhibitor SB-203580 (10 μM) potentiated and prolonged short-circuit current ( I sc) responses to CCh across voltage-clamped T84 cells to 157.4 ± 6.9% of those in control cells ( n = 21; P < 0.001). CCh-induced p38 phosphorylation was attenuated by the EGFR inhibitor tyrphostin AG-1478 (0.1 nM–10 μM) and by the Src family kinase inhibitor PP2 (20 nM–2 μM). The effects of CCh on p38 phosphorylation were mimicked by thapsigargin (TG; 2 μM), which specifically elevates intracellular Ca2+, and were abolished by the Ca2+ chelator BAPTA-AM (20 μM), implying a role for intracellular Ca2+ in mediating p38 activation. SB-203580 (10 μM) potentiated I sc responses to TG to 172.4 ± 18.1% of those in control cells ( n= 18; P < 0.001). When cells were pretreated with SB-203580 and PD-98059 to simultaneously inhibit p38 and ERK MAPKs, respectively, I sc responses to TG and CCh were significantly greater than those observed with either inhibitor alone. We conclude that Ca2+-dependent agonists stimulate p38 MAPK in T84 cells by a mechanism involving intracellular Ca2+, Src family kinases, and the EGFR. CCh-stimulated p38 activation constitutes a similar, but distinct and complementary, antisecretory signaling pathway to that of ERK MAPK.

scholarly journals Effects of ethanol on mitogen-activated protein kinase and stress-activated protein kinase cascades in normal and regenerating liver

1998 ◽  
Vol 334 (3) ◽  
pp. 669-676 ◽  
Author(s):  
Jianping CHEN ◽  
Edward J. N. ISHAC ◽  
Paul DENT ◽  
George KUNOS ◽  
Bin GAO
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Ethanol Exposure ◽  
Selective Inhibitor ◽  
Chronic Ethanol ◽  
Mitogen Activated Protein Kinase ◽  
Hepatocyte Proliferation ◽  
Mapk Activation ◽  
Chronic Ethanol Consumption ◽  
Mitogen Activated Protein

To understand the mechanisms by which ethanol inhibits hepatocyte proliferation, we studied the effects of ethanol on p42/44 mitogen-activated protein kinase (MAPK), p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun N-terminal kinase (JNK) in normal and regenerating rat liver. Treatment of rat hepatocytes with 100 mM ethanol in vitro for 16 h prolonged the activation of p42/44 MAPK and p38 MAPK induced by various agonists. Such treatment also increased basal JNK activity, but did not potentiate or prolong agonist-induced JNK activation. Ethanol potentiation of the activation of p42/44 MAPK was abolished by pertussis toxin. In contrast, chronic ethanol consumption in vivo inhibited the activation of p42/44 MAPK, p38 MAPK and JNK induced either by partial hepatectomy or by various agonists. However, both acute and chronic ethanol inhibited hepatocyte proliferation induced by insulin and epidermal growth factor. A selective inhibitor of p42/44 MAPK partially prevented the inhibition of hepatocyte proliferation caused by acute, but not by chronic, ethanol exposure, whereas a selective inhibitor of p38 MAPK further inhibited hepatocyte proliferation under both conditions. These data suggest that acute and chronic ethanol inhibit hepatocyte proliferation by different mechanisms. The effect of acute ethanol may be related to the prolongation of p42/44 MAPK activation, whereas inhibition of hepatocyte proliferation by chronic ethanol may be due to inhibition of p38 MAPK activation.

scholarly journals Loss of Oncogenic H-ras-Induced Cell Cycle Arrest and p38 Mitogen-Activated Protein Kinase Activation by Disruption of Gadd45a

2003 ◽  
Vol 23 (11) ◽  
pp. 3859-3871 ◽  
Author(s):  
Dmitry V. Bulavin ◽  
Oleg Kovalsky ◽  
M. Christine Hollander ◽  
Albert J. Fornace
Keyword(s):  
Cell Cycle ◽  
Amino Acids ◽  
Protein Kinase ◽  
Cell Cycle Arrest ◽  
P38 Mapk ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Activation ◽  
Cycle Arrest ◽  
Mitogen Activated Protein ◽  
P53 Activation

ABSTRACT The activation of p53 is a guardian mechanism to protect primary cells from malignant transformation; however, the details of the activation of p53 by oncogenic stress are still incomplete. In this report we show that in Gadd45a −/− mouse embryo fibroblasts (MEF), overexpression of H-ras activates extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) but not p38 kinase, and this correlates with the loss of H-ras-induced cell cycle arrest (premature senescence). Inhibition of p38 mitogen-activated protein kinase (MAPK) activation correlated with the deregulation of p53 activation, and both a p38 MAPK chemical inhibitor and the expression of a dominant-negative p38α inhibited p53 activation in the presence of H-ras in wild-type MEF. p38, but not ERK or JNK, was found in a complex with Gadd45 proteins. The region of interaction was mapped to amino acids 71 to 96, and the central portion (amino acids 71 to 124) of Gadd45a was required for p38 MAPK activation in the presence of H-ras. Our results indicate that this Gadd45/p38 pathway plays an important role in preventing oncogene-induced growth at least in part by regulating the p53 tumor suppressor.

Role of p38 mitogen-activated protein kinase pathway in estrogen-mediated cardioprotection following trauma-hemorrhage

2007 ◽  
Vol 292 (6) ◽  
pp. H2982-H2987 ◽  
Author(s):  
Jun-Te Hsu ◽  
Ya-Ching Hsieh ◽  
Wen Hong Kan ◽  
Jian Guo Chen ◽  
Mashkoor A. Choudhry ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cardiac Function ◽  
P38 Mapk ◽  
Mitogen Activated Protein Kinase ◽  
Male Rats ◽  
Mitogen Activated Protein ◽  
Salutary Effect ◽  
The Stability ◽  
Shock Proteins ◽  
Sb 203580

p38 mitogen-activated protein kinase (MAPK) activates a number of heat shock proteins (HSPs), including HSP27 and αB-crystallin, in response to stress. Activation of HSP27 or αB-crystallin is known to protect organs/cells by increasing the stability of actin microfilaments. Although our previous studies showed that 17β-estradiol (E2) improves cardiovascular function after trauma-hemorrhage, whether the salutary effects of E2 under those conditions are mediated via p38 MAPK remains unknown. Male rats (275–325 g body wt) were subjected to soft tissue trauma and hemorrhage (35–40 mmHg mean blood pressure for ∼90 min) followed by fluid resuscitation. At the onset of resuscitation, rats were injected intravenously with vehicle, E2 (1 mg/kg body wt), E2 + the p38 MAPK inhibitor SB-203580 (2 mg/kg body wt), or SB-203580 alone, and various parameters were measured 2 h thereafter. Cardiac functions that were depressed after trauma-hemorrhage were returned to normal levels by E2 administration, and phosphorylation of cardiac p38 MAPK, HSP27, and αB-crystallin was increased. The E2-mediated improvement of cardiac function and increase in p38 MAPK, HSP27, and αB-crystallin phosphorylation were abolished with coadministration of SB-203580. These results suggest that the salutary effect of E2 on cardiac function after trauma-hemorrhage is in part mediated via upregulation of p38 MAPK and subsequent phosphorylation of HSP27 and αB-crystallin.

scholarly journals Cytokine Activation of p38 Mitogen-Activated Protein Kinase and Apoptosis Is Opposed by alpha-4 Targeting of Protein Phosphatase 2A for Site-Specific Dephosphorylation of MEK3

2007 ◽  
Vol 27 (12) ◽  
pp. 4217-4227 ◽  
Author(s):  
Todd D. Prickett ◽  
David L. Brautigan
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Phosphorylation Site ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Activation ◽  
Tnf Α ◽  
Mitogen Activated Protein ◽  
Phosphatase 2A

ABSTRACT alpha-4 is an essential gene and is a dominant antiapoptotic factor in various tissues that is a regulatory subunit for type 2A protein phosphatases. A multiplexed phosphorylation site screen revealed that knockdown of alpha-4 by small interfering RNA (siRNA) increased p38 mitogen-activated protein kinase (MAPK) and c-Jun phosphorylation without changes in JNK or ERK. FLAG-alpha-4 coprecipitated hemagglutinin-MEK3 plus endogenous protein phosphatase 2A (PP2A) and selectively enhanced dephosphorylation of Thr193, but not Ser189, in the activation loop of MEK3. Overexpression of alpha-4 suppressed p38 MAPK activation in response to tumor necrosis factor alpha (TNF-α). The alpha-4 dominant-negative domain (DND) (residues 220 to 340) associated with MEK3, but not PP2A, and its overexpression sensitized cells to activation of p38 MAPK by TNF-α and interleukin-1β, but not by ansiomycin or sorbitol. The response was diminished by nocodazole or by siRNA knockdown of the Opitz syndrome protein Mid1 that binds alpha-4 to microtubules. Interference by alpha-4 DND or alpha-4 siRNA increased caspase 3/7 activation in response to TNF-α. Growth of transformed cells in soft agar was enhanced by alpha-4 and suppressed by alpha-4 DND. The results show that alpha-4 targets PP2A activity to MEK3 to suppress p38 MAPK activation by cytokines, thereby inhibiting apoptosis and anoikis.

TGF-β1 stimulates HO-1 via the p38 mitogen-activated protein kinase in A549 pulmonary epithelial cells

2002 ◽  
Vol 283 (5) ◽  
pp. L1094-L1102 ◽  
Author(s):  
Wen Ning ◽  
Ruiping Song ◽  
Chaojun Li ◽  
Edward Park ◽  
Amir Mohsenin ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Epithelial Cells ◽  
Mrna Expression ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
A549 Cells ◽  
Mitogen Activated Protein Kinase ◽  
P38 Mapk Pathway ◽  
Mitogen Activated Protein ◽  
Sb 203580

In lung injury and progressive lung diseases, the multifunctional cytokine transforming growth factor-β1 (TGF-β1) modulates inflammatory responses and wound repair. Heme oxygenase-1 (HO-1) is a stress-inducible protein that has been demonstrated to confer cytoprotection against oxidative injury and provide a vital function in maintaining tissue homeostasis. Here we report that TGF-β1 is a potent inducer of HO-1 and examined the signaling pathway by which TGF-β1 regulates HO-1 expression in human lung epithelial cells (A549). TGF-β1(1–5 ng/ml) treatment resulted in a marked time-dependent induction of HO-1 mRNA in A549 cells, followed by corresponding increases in HO-1 protein and HO enzymatic activity. Actinomycin D and cycloheximide inhibited TGF-β1-responsive HO-1 mRNA expression, indicating a requirement for transcription and de novo protein synthesis. Furthermore, TGF-β1 rapidly activated the p38 mitogen-activated protein kinase (p38 MAPK) pathway in A549 cells. A chemical inhibitor of p38 MAPK (SB-203580) abolished TGF-β1-inducible HO-1 mRNA expression. Both SB-203580 and expression of a dominant-negative mutant of p38 MAPK inhibited TGF-β1-induced ho-1 gene activation, as assayed by luciferase activity of an ho-1enhancer/luciferase fusion construct (pMHO1luc-33+SX2). These studies demonstrate the critical intermediacy of the p38 MAPK pathway in the regulation of HO-1 expression by TGF-β1.

scholarly journals Hematopoietic Protein Tyrosine Phosphatase Mediates β2-Adrenergic Receptor-Induced Regulation of p38 Mitogen-Activated Protein Kinase in B Lymphocytes

2008 ◽  
Vol 29 (3) ◽  
pp. 675-686 ◽  
Author(s):  
Jaclyn W. McAlees ◽  
Virginia M. Sanders
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Protein Tyrosine Phosphatase ◽  
Adrenergic Receptor ◽  
Tyrosine Phosphatase ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Mapk Activation ◽  
Mapk Phosphorylation ◽  
Mitogen Activated Protein

ABSTRACT Stimulation of the β2-adrenergic receptor (β2AR) on a CD40L/interleukin-4-activated B lymphocyte increases the level of immunoglobulin E (IgE) in a protein kinase A (PKA)- and p38 mitogen-activated protein kinase (MAPK)-dependent manner. However, the mechanism by which β2AR stimulation mediates the increase in the level of p38 MAPK activation has remained unclear. Here we show that the β2AR-induced increase in p38 MAPK activation occurred via a hematopoietic protein tyrosine phosphatase (HePTP)-mediated cross talk between PKA and p38 MAPK. β2AR agonists, cAMP-elevating agents, and PKA inhibitors were used to show that β2AR stimulation resulted in a PKA-dependent increase in p38 MAPK phosphorylation. Pharmacological agents and gene-deficient mice revealed that p38 MAPK phosphorylation was regulated by the G-stimulatory (Gs)/cAMP/PKA pathway independently of the G-inhibitory or β-arrestin-2 pathways. Coimmunoprecipitation and Western blot analysis showed that HePTP was phosphorylated in a PKA-dependent manner, which inactivated HePTP and allowed for increased free p38 MAPK to be phosphorylated by the MAPK cascade that was activated by CD40L. HePTP short hairpin RNA confirmed that HePTP played a role in regulating the level of p38 MAPK phosphorylation in a B cell. Thus, β2AR stimulation on a B cell phosphorylates and inactivates HePTP in a Gs/cAMP/PKA-dependent manner to release bound p38 MAPK, making more available for phosphorylation and subsequent IgE regulation.

scholarly journals Drugs Designed To Inhibit Human p38 Mitogen-Activated Protein Kinase Activation Treat Toxoplasma gondii and Encephalitozoon cuniculi Infection

2007 ◽  
Vol 51 (12) ◽  
pp. 4324-4328 ◽  
Author(s):  
Shuang Wei ◽  
Benjamin J. Daniel ◽  
Michael J. Brumlik ◽  
Matthew E. Burow ◽  
Weiping Zou ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Toxoplasma Gondii ◽  
P38 Mapk ◽  
Human Fibroblasts ◽  
Mitogen Activated Protein Kinase ◽  
Encephalitozoon Cuniculi ◽  
Mapk Activation ◽  
Mitogen Activated Protein ◽  
P38 Mapk Inhibitors ◽  
Mapk Inhibitors

ABSTRACT We recently showed that the pyridinylimidazoles SB203580 and SB202190, drugs designed to block human p38 mitogen-activated protein kinase (MAPK) activation, also inhibited replication of the medically important intracellular parasite Toxoplasma gondii in cultured human fibroblasts through a direct effect on the parasite. We now show that additional pyridinylimidazole and imidazopyrimidine p38 MAPK inhibitors inhibit intracellular T. gondii replication in vitro and protect mice against fatal T. gondii infection. Mice surviving infection following treatment with p38 MAPK inhibitors were resistant to subsequent T. gondii challenge, demonstrating induction of protective immunity. Thus, drugs originally developed to block human p38 MAPK activation are useful for treating T. gondii infection without inducing significant immunosuppression. MAPK inhibitors combined with either of the approved anti-Toxoplasma drugs sulfadiazine and pyrimethamine resulted in improved survival among mice challenged with a fatal T. gondii inoculum. A MAPK inhibitor also treated mice infected with the Microsporidium parasite Encephalitozoon cuniculi, suggesting that MAPK inhibitors represent a novel class of agents that may have a broad spectrum of antiparasitic activity. Preliminary studies implicate a T. gondii MAPK homologue as the target of drug action, suggesting possibilities for more-selective agents.

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