scholarly journals p38 Mitogen-Activated Protein Kinase (MAPK) Is a Key Mediator in Glucocorticoid-Induced Apoptosis of Lymphoid Cells: Correlation between p38 MAPK Activation and Site-Specific Phosphorylation of the Human Glucocorticoid Receptor at Serine 211

2005 ◽  
Vol 19 (6) ◽  
pp. 1569-1583 ◽  
Author(s):  
Aaron L. Miller ◽  
M. Scott Webb ◽  
Alicja J. Copik ◽  
Yongxin Wang ◽  
Betty H. Johnson ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Mapk Signaling ◽  
Lymphoid Cells ◽  
Mitogen Activated Protein Kinase ◽  
Enzymatic Assays ◽  
Mapk Activity ◽  
Mitogen Activated Protein ◽  
Elevated Activity ◽  
Induced Apoptosis

Abstract Glucocorticoids (GCs) induce apoptosis in lymphoid cells through activation of the GC receptor (GR). We have evaluated the role of p38, a MAPK, in lymphoid cell apoptosis upon treatment with the synthetic GCs dexamethasone (Dex) or deacylcortivazol (DAC). The highly conserved phosphoprotein p38 MAPK is activated by specific phosphorylation of its threonine180 and tyrosine182 residues. We show that Dex and DAC stimulate p38 MAPK phosphorylation and increase the mRNA of MAPK kinase 3, a specific immediate upstream activator of p38 MAPK. Enzymatic assays confirmed elevated activity of p38 MAPK. Pharmacological inhibition of p38 MAPK activity was protective against GC-driven apoptosis in human and mouse lymphoid cells. In contrast, inhibition of the MAPKs, ERK and cJun N-terminal kinase, enhanced apoptosis. Activated p38 MAPK phosphorylates specific downstream targets. Because phosphorylation of the GR is affected by MAPKs, we examined its phosphorylation state in our system. We found serine 211 of the human GR to be a substrate for p38 MAPK both in vitro and intracellularly. Mutation of this site to alanine greatly diminished GR-driven gene transcription and apoptosis. Our results clearly demonstrate a role for p38 MAPK signaling in the pathway of GC-induced apoptosis of lymphoid cells.

scholarly journals Fever-like temperature modification differentially affects in vitro signaling of bradykinin B1 and B2 receptors

2011 ◽  
Vol 392 (11) ◽  
Author(s):  
Jasmin Leschner ◽  
Larisa Ring ◽  
Jens Feierler ◽  
Klaus Dinkel ◽  
Marianne Jochum ◽  
...  
Keyword(s):  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Temperature Sensitive ◽  
Hek 293 ◽  
Mapk Activity ◽  
Mitogen Activated Protein ◽  
Surface Receptor ◽  
B2 Receptors ◽  
Stimulation Of

Abstract The bradykinin (BK) B2 and B1 receptors (B2R, B1R) belong to the rhodopsin-like G protein-coupled receptors (GPCRs) and are involved in (patho)physiological processes such as blood pressure regulation or inflammation. They mediate the effects of the pro-inflammatory peptides bradykinin/kallidin and desArg9-BK/desArg10-kallidin, respectively. Whereas the B2R is constitutively expressed and gets internalized upon activation, the B1R is especially induced by inflammatory mediators and responds to stimulation with increased surface receptor numbers. Stimulation of both receptors activates phospholipase Cβ (PLCβ) and mitogen activated protein kinase (MAPK) signaling. Because inflammatory processes are characterized by heat (fever), we analyzed the effect of increased temperature (41°C vs. 37°C) on B1R and B2R signaling in HEK 293 and IMR 90 cells. Our results show that signaling of both receptors is temperature-sensitive, however to a different extent and with regard to the investigated pathways. Comparing PLCβ activity and Ca2+-regulated signals, a temperature-dependent increase was only observed for B1R but not for B2R activation, whereas MAPK activities were doubled at 41°C for both receptors. Taken together, our findings suggest that the observed temperature sensitivity of B1R-induced PLCβ activation is B1R-specific. In contrast, the enhanced stimulation of MAPK activity under hyperthermic conditions appears to be a common phenomenon for GPCRs.

scholarly journals Selective Regulation of c-jun Gene Expression by Mitogen-Activated Protein Kinases via the 12-O-Tetradecanoylphorbol-13-Acetate- Responsive Element and Myocyte Enhancer Factor 2 Binding Sites

2005 ◽  
Vol 25 (9) ◽  
pp. 3784-3792 ◽  
Author(s):  
Midori Kayahara ◽  
Xin Wang ◽  
Cathy Tournier
Keyword(s):  
Gene Expression ◽  
Protein Kinase ◽  
Cell Fate ◽  
P38 Mapk ◽  
Physiological Role ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Cascades ◽  
Mitogen Activated Protein

ABSTRACT To further understand how the mitogen-activated protein kinase (MAPK) signaling pathways regulate AP-1 activity, we have elucidated the physiological role of these cascades in the regulation of c-jun gene expression. c-Jun is a crucial component of AP-1 complexes and has been shown in vitro to be a point of integration of numerous signals that can differentially affect its expression as well as its transcriptional activity. Our strategy was based on the use of (i) genetically modified fibroblasts deficient in components of the MAPK cascades and (ii) pharmacological reagents. The results demonstrate that c-Jun NH2-terminal protein kinase (JNK) is essential for a basal level of c-Jun expression and for c-Jun phosphorylation in response to stress. In addition to JNK, p38 MAPK or ERK1/2 and ERK5 are required for mediating UV radiation- or epidermal growth factor (EGF)-induced c-Jun expression, respectively. Further studies indicate that p38 MAPK inhibits the activation of JNK in response to EGF, causing a down-regulation of c-Jun. Overall, these data provide important insights into the mechanisms that ultimately determine the function of c-Jun as a regulator of cell fate.

scholarly journals p38-MAPK Signals Survival by Phosphorylation of Caspase-8 and Caspase-3 in Human Neutrophils

2004 ◽  
Vol 199 (4) ◽  
pp. 449-458 ◽  
Author(s):  
Maria Alvarado-Kristensson ◽  
Fredrik Melander ◽  
Karin Leandersson ◽  
Lars Rönnstrand ◽  
Christer Wernstedt ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Caspase 3 ◽  
Mitogen Activated Protein Kinase ◽  
Human Neutrophils ◽  
Caspase 8 ◽  
Neutrophil Apoptosis ◽  
Mapk Activity ◽  
Mitogen Activated Protein ◽  
Phosphopeptide Mapping

Neutrophil apoptosis occurs both in the bloodstream and in the tissue and is considered essential for the resolution of an inflammatory process. Here, we show that p38–mitogen-activated protein kinase (MAPK) associates to caspase-8 and caspase-3 during neutrophil apoptosis and that p38-MAPK activity, previously shown to be a survival signal in these primary cells, correlates with the levels of caspase-8 and caspase-3 phosphorylation. In in vitro experiments, immunoprecipitated active p38-MAPK phosphorylated and inhibited the activity of the active p20 subunits of caspase-8 and caspase-3. Phosphopeptide mapping revealed that these phosphorylations occurred on serine-364 and serine-150, respectively. Introduction of mutated (S150A), but not wild-type, TAT-tagged caspase-3 into primary neutrophils made the Fas-induced apoptotic response insensitive to p38-MAPK inhibition. Consequently, p38-MAPK can directly phosphorylate and inhibit the activities of caspase-8 and caspase-3 and thereby hinder neutrophil apoptosis, and, in so doing, regulate the inflammatory response.

scholarly journals Essential role of p53 phosphorylation by p38 MAPK in apoptosis induction by the HIV-1 envelope

2005 ◽  
Vol 201 (2) ◽  
pp. 279-289 ◽  
Author(s):  
Jean-Luc Perfettini ◽  
Maria Castedo ◽  
Roberta Nardacci ◽  
Fabiola Ciccosanti ◽  
Patricia Boya ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Target Genes ◽  
Dominant Negative ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Model Cell ◽  
Induced Apoptosis ◽  
Hiv 1

The proapoptotic activity of the transcription factor p53 critically depends on the phosphorylation of serine 46 (p53S46P). Here, we show that syncytia containing p53S46P could be detected in lymph node biopsies from human immunodeficiency virus (HIV)-1 carriers, in the brain of patients with HIV-1–associated dementia and in cocultures of HeLa expressing the HIV-1 envelope glycoprotein complex (Env) with HeLa cells expressing CD4. In this latter model, cell death was the result of a sequential process involving cell fusion, nuclear fusion (karyogamy), phosphorylation of serine 15 (p53S15P), later on serine 46 (p53S46P), and transcription of p53 target genes. Cytoplasmic p38 mitogen-activated protein kinase (MAPK) was found to undergo an activating phosphorylation (p38T180/Y182P [p38 with phosphorylated threonine 180 and tyrosine 182]) before karyogamy and to translocate into karyogamic nuclei. p38T180/Y182P colocalized and coimmunoprecipitated with p53S46P. Recombinant p38 phosphorylated recombinant p53 on serine 46 in vitro. Inhibition of p38 MAPK by pharmacological inhibitors, dominant-negative p38, or small interfering RNA, suppressed p53S46P (but not p53S15P), the expression of p53-inducible genes, the conformational activation of proapoptotic Bax and Bak, the release of cytochrome c from mitochondria, and consequent apoptosis. p38T180/Y182P was also detected in HIV-1–induced syncytia, in vivo, in patients' lymph nodes and brains. Dominant-negative MKK3 or MKK6 inhibited syncytial activation of p38, p53S46P, and apoptosis. Altogether, these findings indicate that p38 MAPK-mediated p53 phosphorylation constitutes a critical step of Env-induced apoptosis.

scholarly journals p38 Mitogen-Activated Protein Kinase Mediates the Fas-Induced Mitochondrial Death Pathway in CD8+ T Cells

2006 ◽  
Vol 26 (6) ◽  
pp. 2118-2129 ◽  
Author(s):  
Nicholas Farley ◽  
Gustavo Pedraza-Alva ◽  
Diego Serrano-Gomez ◽  
Viswas Nagaleekar ◽  
Alexander Aronshtam ◽  
...  
Keyword(s):  
T Cells ◽  
Protein Kinase ◽  
P38 Mapk ◽  
Fas Ligand ◽  
Death Receptor ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Mitochondrial Death Pathway ◽  
Induced Apoptosis

ABSTRACT The p38 mitogen-activated protein kinase (MAPK) signaling pathway can be activated by a variety of stress stimuli such as UV radiation and osmotic stress. The regulation and role of this pathway in death receptor-induced apoptosis remain unclear and may depend on the specific death receptor and cell type. Here we show that binding of Fas ligand to Fas activates p38 MAPK in CD8+ T cells and that activation of this pathway is required for Fas-mediated CD8+ T-cell death. Active p38 MAPK phosphorylates Bcl-xL and Bcl-2 and prevents the accumulation of these antiapoptotic molecules within the mitochondria. Consequently, a loss of mitochondrial membrane potential and the release of cytochrome c lead to the activation of caspase 9 and, subsequently, caspase 3. Therefore, the activation of p38 MAPK is a critical link between Fas and the mitochondrial death pathway and is required for the Fas-induced apoptosis of CD8+ T cells.

scholarly journals Interleukin-6 Inhibits Fas-Induced Apoptosis and Stress-Activated Protein Kinase Activation in Multiple Myeloma Cells

Blood ◽  
1997 ◽  
Vol 89 (1) ◽  
pp. 227-234 ◽  
Author(s):  
Dharminder Chauhan ◽  
Surender Kharbanda ◽  
Atsushi Ogata ◽  
Mitsuyoshi Urashima ◽  
Gerrard Teoh ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Protein Kinase ◽  
Dna Fragmentation ◽  
P38 Mapk ◽  
Interleukin 6 ◽  
Early Response ◽  
Mitogen Activated Protein Kinase ◽  
Serum Starvation ◽  
Mapk Activity ◽  
Induced Apoptosis

Abstract Fas belongs to the family of type-1 membrane proteins that transduce apoptotic signals. In the present studies, we characterized signaling during Fas-induced apoptosis in RPMI-8226 and IM-9 multiple myeloma (MM) derived cell lines as well as patient plasma cell leukemia cells. Treatment with anti-Fas (7C11) monoclonal antibody (MoAb) induced apoptosis, evidenced by internucleosomal DNA fragmentation and propidium iodide staining, and was associated with increased expression of c-jun early response gene. We also show that anti-Fas MoAb treatment is associated with activation of stress-activated protein kinase (SAPK) and p38 mitogen-activated protein kinase (MAPK); however, no detectable increase in extracellular signal-regulated kinases (ERK1 and ERK2) activity was observed. Because interleukin-6 (IL-6) is a growth factor for MM cells and inhibits apoptosis induced by dexamethasone and serum starvation, we examined whether IL-6 affects anti-Fas MoAb-induced apoptosis and activation of SAPK or p38 MAPK in MM cells. Culture of MM cells with IL-6 before treatment with anti-Fas MoAb significantly reduced both DNA fragmentation and activation of SAPK, without altering induction of p38 MAPK activity. These results therefore suggest that anti-Fas MoAb-induced apoptosis in MM cells is associated with activation of SAPK, and that IL-6 may both inhibit apoptosis and modulate SAPK activity.

scholarly journals Cross-talk between IRAK-4 and the NADPH oxidase1

2007 ◽  
Vol 403 (3) ◽  
pp. 451-461 ◽  
Author(s):  
Sandrine Pacquelet ◽  
Jennifer L. Johnson ◽  
Beverly A. Ellis ◽  
Agnieszka A. Brzezinska ◽  
William S. Lane ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Nadph Oxidase ◽  
P38 Mapk ◽  
Interleukin 1 ◽  
Mitogen Activated Protein Kinase ◽  
Free System ◽  
Mitogen Activated Protein ◽  
A Cell ◽  
Tlr4 Activation

Exposure of neutrophils to LPS (lipopolysaccharide) triggers their oxidative response. However, the relationship between the signalling downstream of TLR4 (Toll-like receptor 4) after LPS stimulation and the activation of the oxidase remains elusive. Phosphorylation of the cytosolic factor p47phox is essential for activation of the NADPH oxidase. In the present study, we examined the hypothesis that IRAK-4 (interleukin-1 receptor-associated kinase-4), the main regulatory kinase downstream of TLR4 activation, regulates the NADPH oxidase through phosphorylation of p47phox. We show that p47phox is a substrate for IRAK-4. Unlike PKC (protein kinase C), IRAK-4 phosphorylates p47phox not only at serine residues, but also at threonine residues. Target residues were identified by tandem MS, revealing a novel threonine-rich regulatory domain. We also show that p47phox is phosphorylated in granulocytes in response to LPS stimulation. LPS-dependent phosphorylation of p47phox was enhanced by the inhibition of p38 MAPK (mitogen-activated protein kinase), confirming that the kinase operates upstream of p38 MAPK. IRAK-4-phosphorylated p47phox activated the NADPH oxidase in a cell-free system, and IRAK-4 overexpression increased NADPH oxidase activity in response to LPS. We have shown that endogenous IRAK-4 interacts with p47phox and they co-localize at the plasma membrane after LPS stimulation, using immunoprecipitation assays and immunofluorescence microscopy respectively. IRAK-4 was activated in neutrophils in response to LPS stimulation. We found that Thr133, Ser288 and Thr356, targets for IRAK-4 phosphorylation in vitro, are also phosphorylated in endogenous p47phox after LPS stimulation. We conclude that IRAK-4 phosphorylates p47phox and regulates NADPH oxidase activation after LPS stimulation.

MKK3-p38 signaling promotes apoptosis and the early inflammatory response in the obstructed mouse kidney

2007 ◽  
Vol 293 (5) ◽  
pp. F1556-F1563 ◽  
Author(s):  
Frank Y. Ma ◽  
Greg H. Tesch ◽  
Richard A. Flavell ◽  
Roger J. Davis ◽  
David J. Nikolic-Paterson
Keyword(s):  
Inflammatory Response ◽  
P38 Mapk ◽  
Renal Injury ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Mrna Levels ◽  
Direct Role ◽  
Mitogen Activated Protein ◽  
Early Inflammatory Response ◽  
Induced Apoptosis

Activation of the p38 mitogen-activated protein kinase (MAPK) pathway induces inflammation, apoptosis, and fibrosis. However, little is known of the contribution of the upstream kinases, MMK3 and MKK6, to activation of the p38 kinase in the kidney and consequent renal injury. This study investigated the contribution of MKK3 to p38 MAPK activation and renal injury in the obstructed kidney. Groups of eight wild-type (WT) or Mkk3−/− mice underwent unilateral ureteric obstruction (UUO) and were killed 3 or 7 days later. Western blotting showed a marked increase in phospho-p38 (p-p38) MAPK in UUO WT kidney. The same trend of increased p-p38 MAPK was seen in the UUO Mkk3−/− kidney, although the actual level of p-p38 MAPK was significantly reduced compared with WT, and this could not be entirely compensated for by the increase in MKK6 expression in the Mkk3−/− kidney. Apoptosis of tubular and interstitial cells in WT UUO mice was reduced by 50% in Mkk3−/− UUO mice. Furthermore, cultured Mkk3−/− tubular epithelial cells showed resistance to H2O2-induced apoptosis, suggesting a direct role for MKK3-p38 signaling in tubular apoptosis. Upregulation of MCP-1 mRNA levels and macrophage infiltration seen on day 3 in WT UUO mice was significantly reduced in Mkk3−/− mice, but this difference was not evident by day 7. The development of renal fibrosis in Mkk3−/− UUO mice was not different from that seen in WT UUO mice. In conclusion, these studies identify discrete roles for MKK3-p38 signaling in renal cell apoptosis and the early inflammatory response in the obstructed kidney.

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.

scholarly journals Understanding MAPK Signaling Pathways in Apoptosis

2020 ◽  
Vol 21 (7) ◽  
pp. 2346 ◽  
Author(s):  
Jicheng Yue ◽  
José M. López
Keyword(s):  
Signaling Pathways ◽  
Positive Feedback ◽  
Cell Model ◽  
Mapk Signaling ◽  
Feedback Loops ◽  
Mitogen Activated Protein Kinase ◽  
Cellular Mechanisms ◽  
Mitogen Activated Protein ◽  
Induced Apoptosis ◽  
Mapk Signaling Pathways

MAPK (mitogen-activated protein kinase) signaling pathways regulate a variety of biological processes through multiple cellular mechanisms. In most of these processes, such as apoptosis, MAPKs have a dual role since they can act as activators or inhibitors, depending on the cell type and the stimulus. In this review, we present the main pro- and anti-apoptotic mechanisms regulated by MAPKs, as well as the crosstalk observed between some MAPKs. We also describe the basic signaling properties of MAPKs (ultrasensitivity, hysteresis, digital response), and the presence of different positive feedback loops in apoptosis. We provide a simple guide to predict MAPKs’ behavior, based on the intensity and duration of the stimulus. Finally, we consider the role of MAPKs in osmostress-induced apoptosis by using Xenopus oocytes as a cell model. As we will see, apoptosis is plagued with multiple positive feedback loops. We hope this review will help to understand how MAPK signaling pathways engage irreversible cellular decisions.

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