scholarly journals p38 Mitogen-Activated Protein Kinase Mediates Cell Death and p21-Activated Kinase Mediates Cell Survival during Chemotherapeutic Drug-induced Mitotic Arrest

2003 ◽  
Vol 14 (5) ◽  
pp. 2071-2087 ◽  
Author(s):  
Karl Deacon ◽  
Pratibha Mistry ◽  
Jonathan Chernoff ◽  
Jonathan L. Blank ◽  
Rajnikant Patel
Keyword(s):  
Cell Death ◽  
Protein Kinase ◽  
Cell Survival ◽  
P38 Mapk ◽  
Mitogen Activated Protein Kinase ◽  
Chemotherapeutic Drugs ◽  
Chemotherapeutic Drug ◽  
Drug Induced ◽  
Mitogen Activated Protein ◽  
P21 Activated Kinase

Activation of the mitotic checkpoint by chemotherapeutic drugs such as taxol causes mammalian cells to arrest in mitosis and then undergo apoptosis. However, the biochemical basis of chemotherapeutic drug-induced cell death is unclear. Herein, we provide new evidence that both cell survival and cell death-signaling pathways are concomitantly activated during mitotic arrest by microtubule-interfering drugs. Treatment of HeLa cells with chemotherapeutic drugs activated both p38 mitogen-activated protein kinase (MAPK) and p21-activated kinase (PAK). p38 MAPK was necessary for chemotherapeutic drug-induced cell death because the p38 MAPK inhibitors SB203580 or SB202190 suppressed cell death. Dominant-active MKK6, a direct activator of p38 MAPK, also induced cell death by stimulating translocation of Bax from the cytosol to the mitochondria in a p38 MAPK-dependent manner. Dominant active PAK suppressed this MKK6-induced cell death. PAK seems to mediate cell survival by phosphorylating Bad, and inhibition of PAK in mitotically arrested cells reduced Bad phosphorylation and increased apoptosis. Our results suggest that therapeutic strategies that suppress PAK-mediated survival signals may improve the efficacy of current cancer chemotherapies by enhancing p38 MAPK-mediated cell death.

scholarly journals Regulation of FAS Ligand Expression during Activation-Induced Cell Death in T Cells by p38 Mitogen-Activated Protein Kinase and C-Jun Nh2-Terminal Kinase

2000 ◽  
Vol 191 (6) ◽  
pp. 1017-1030 ◽  
Author(s):  
Jian Zhang ◽  
Jian-Xin Gao ◽  
Kostantin Salojin ◽  
Qing Shao ◽  
Marsha Grattan ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Protein Kinase ◽  
P38 Mapk ◽  
Fas Ligand ◽  
Mitogen Activated Protein Kinase ◽  
Fasl Expression ◽  
Activation Induced Cell Death ◽  
Mitogen Activated Protein

Activation-induced cell death (AICD) is a mechanism of peripheral T cell tolerance that depends upon an interaction between Fas and Fas ligand (FasL). Although c-Jun NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) may be involved in apoptosis in various cell types, the mode of regulation of FasL expression during AICD in T cells by these two MAPKs is incompletely understood. To investigate the regulatory roles of these two MAPKs, we analyzed the kinetics of TCR-induced p38 MAPK and JNK activity and their regulation of FasL expression and AICD. We report that both JNK and p38 MAPK regulate AICD in T cells. Our data suggest a novel model of T cell AICD in which p38 MAPK acts early to initiate FasL expression and the Fas-mediated activation of caspases. Subsequently, caspases stimulate JNK to further upregulate FasL expression. Thus, p38 MAPK and downstream JNK converge to regulate FasL expression at different times after T cell receptor stimulation to elicit maximum AICD.

scholarly journals FAS Ligand, Bcl-2, Granulocyte Colony-Stimulating Factor, and p38 Mitogen-Activated Protein Kinase

2000 ◽  
Vol 192 (5) ◽  
pp. 647-658 ◽  
Author(s):  
Andreas Villunger ◽  
Lorraine A. O'Reilly ◽  
Nils Holler ◽  
Jerry Adams ◽  
Andreas Strasser
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Fas Ligand ◽  
Mitogen Activated Protein Kinase ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Drug Induced ◽  
Mitogen Activated Protein ◽  
Induced Apoptosis ◽  
Stimulating Factor

The short life span of granulocytes, which limits many inflammatory responses, is thought to be influenced by the Bcl-2 protein family, death receptors such as CD95 (Fas/APO-1), stress-activated protein kinases such as p38 mitogen-activated protein kinase (MAPK), and proinflammatory cytokines like granulocyte colony-stimulating factor (G-CSF). To clarify the roles of these various regulators in granulocyte survival, we have investigated the spontaneous apoptosis of granulocytes in culture and that induced by Fas ligand or chemotherapeutic drugs, using cells from normal, CD95-deficient lpr, or vav-bcl-2 transgenic mice. CD95-induced apoptosis, which required receptor aggregation by recombinant Fas ligand or the membrane-bound ligand, was unaffected by G-CSF treatment or Bcl-2 overexpression. Conversely, spontaneous and drug-induced apoptosis occurred normally in lpr granulocytes but were suppressed by G-CSF treatment or Bcl-2 overexpression. Although activation of p38 MAPK has been implicated in granulocyte death, their apoptosis actually was markedly accelerated by specific inhibitors of this kinase. These results suggest that G-CSF promotes granulocyte survival largely through the Bcl-2–controlled pathway, whereas CD95 regulates a distinct pathway to apoptosis that is not required for either their spontaneous or drug-induced death. Moreover, p38 MAPK signaling contributes to granulocyte survival rather than their apoptosis.

Resveratrol protects H9c2 embryonic rat heart derived cells from oxidative stress by inducing autophagy: role of p38 mitogen-activated protein kinase

2012 ◽  
Vol 90 (5) ◽  
pp. 655-662 ◽  
Author(s):  
Xiao Cui Lv ◽  
Hai Yan Zhou
Keyword(s):  
Oxidative Stress ◽  
Protein Kinase ◽  
Cell Survival ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Protective Effects ◽  
H9c2 Cells ◽  
P38 Mapk Pathway ◽  
Mitogen Activated Protein

Recently, many studies have attempted to illustrate the mechanism of autophagy in protection against oxidative stress to the heart induced by H2O2. However, whether resveratrol-induced autophagy involves the p38 mitogen-activated protein kinase (MAPK) pathway is still unknown. This study aimed to investigate whether treating H9c2 cells with resveratrol increases autophagy and attenuates the cell death and apoptosis induced by oxidative stress via the p38 MAPK pathway. Resveratrol with or without SB202190, an inhibitor of the p38 MAPK pathway, was added 30 min before H2O2. After H2O2 treatment, the cells were incubated under 5% CO2 at 37 °C for 24 h to assess cell survival and death or incubated for 20 min for Western blot and transmission electron microscopy. Flow cytometry was used to detect apoptosis after 6 h of H2O2 treatment. Resveratrol at 20 µmol/L protected H9c2 cells treated with 100 µmol/L H2O2 from oxidative damage. It increased cell survival and markedly decrease lactate dehydrogenase release. In addition, resveratrol increased autophagy and decreased H2O2-induced apoptosis. Furthermore, the protective effects of resveratrol were inhibited by 10 µmol/L SB202190. Thus, resveratrol protected H2O2-treated H9c2 cells by upregulating autophagy via the p38 MAPK pathway.

scholarly journals Mitogen-Activated Protein Kinase Feedback Phosphorylation Regulates MEK1 Complex Formation and Activation during Cellular Adhesion

2004 ◽  
Vol 24 (6) ◽  
pp. 2308-2317 ◽  
Author(s):  
Scott T. Eblen ◽  
Jill K. Slack-Davis ◽  
Adel Tarcsafalvi ◽  
J. Thomas Parsons ◽  
Michael J. Weber ◽  
...  
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Complex Formation ◽  
Feedback System ◽  
Cellular Adhesion ◽  
Feedback Mechanism ◽  
Mitogen Activated Protein Kinase ◽  
Integrin Signaling ◽  
Mitogen Activated Protein ◽  
P21 Activated Kinase

ABSTRACT Cell adhesion and spreading depend on activation of mitogen-activated kinase, which in turn is regulated both by growth factor and integrin signaling. Growth factors, such as epidermal growth factor, are capable of activating Ras and Raf, but integrin signaling is required to couple Raf to MEK and MEK to extracellular signal-regulated protein kinase (ERK). It was previously shown that Rac-p21-activated kinase (PAK) signaling regulated the physical association of MEK1 with ERK2 through phosphorylation sites in the proline-rich sequence (PRS) of MEK1. It was also shown that activation of MEK1 and ERK by integrins depends on PAK phosphorylation of S298 in the PRS. Here we report a novel MEK1-specific regulatory feedback mechanism that provides a means by which activated ERK can terminate continued PAK phosphorylation of MEK1. Activated ERK can phosphorylate T292 in the PRS, and this blocks the ability of PAK to phosphorylate S298 and of Rac-PAK signaling to enhance MEK1-ERK complex formation. Preventing ERK feedback phosphorylation on T292 during cellular adhesion prolonged phosphorylation of S298 by PAK and phosphorylation of S218 and S222, the MEK1 activating sites. We propose that activation of ERK during adhesion creates a feedback system in which ERK phosphorylates MEK1 on T292, and this in turn blocks additional S298 phosphorylation in response to integrin signaling.

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.

Sign in / Sign up

Export Citation Format

Share Document