Adaphostin promotes caffeine-evoked autocrine Fas-mediated death pathway activation in Bcr/Abl-positive leukaemia cells

2011 ◽  
Vol 439 (3) ◽  
pp. 453-470 ◽  
Author(s):  
Wen-Hsin Liu ◽  
Long-Sen Chang
Keyword(s):  
P38 Mapk ◽  
K562 Cells ◽  
Mitogen Activated Protein Kinase ◽  
Pathway Activation ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
P38α Mapk ◽  
Activating Transcription Factor ◽  
Leukaemia Therapy ◽  
Jnk Activation

The present study was conducted to verify whether caffeine is beneficial for improving leukaemia therapy. Co-treatment with adaphostin (a Bcr/Abl inhibitor) was found to potentiate caffeine-induced Fas/FasL up-regulation. Although adaphostin did not elicit ASK1 (apoptosis signal-regulating kinase 1)-mediated phosphorylation of p38 MAPK (mitogen-activated protein kinase) and JNK (c-Jun N-terminal kinase), co-treatment with adaphostin notably increased p38 MAPK/JNK activation in caffeine-treated cells. Suppression of p38 MAPK and JNK abrogated Fas/FasL up-regulation in caffeine- and caffeine/adaphostin-treated cells. Compared with caffeine, adaphostin markedly suppressed Akt/ERK (extracellular-signal-regulated kinase)-mediated MKP-1 (MAPK phosphatase 1) protein expression in K562 cells. MKP-1 down-regulation eventually elucidated the enhanced effect of adaphostin on p38 MAPK/JNK activation and subsequent Fas/FasL up-regulation in caffeine-treated cells. Knockdown of p38α MAPK and JNK1, ATF-2 (activating transcription factor 2) and c-Jun by siRNA (small interfering RNA) proved that p38α MAPK/ATF-2 and JNK1/c-Jun pathways were responsible for caffeine-evoked Fas/FasL up-regulation. Moreover, Ca2+ and ROS (reactive oxygen species) were demonstrated to be responsible for ASK1 activation and Akt/ERK inactivation respectively in caffeine- and caffeine/adaphostin-treated cells. Likewise, adaphostin functionally enhanced caffeine-induced Fas/FasL up-regulation in leukaemia cells that expressed Bcr/Abl. Taken together, the results of the present study suggest a therapeutic strategy in improving the efficacy of adaphostin via Fas-mediated death pathway activation in Bcr/Abl-positive leukaemia.

scholarly journals Helicobacter pylori VacA Enhances Prostaglandin E2 Production through Induction of Cyclooxygenase 2 Expression via a p38 Mitogen-Activated Protein Kinase/Activating Transcription Factor 2 Cascade in AZ-521 Cells

2007 ◽  
Vol 75 (9) ◽  
pp. 4472-4481 ◽  
Author(s):  
Junzo Hisatsune ◽  
Eiki Yamasaki ◽  
Masaaki Nakayama ◽  
Daisuke Shirasaka ◽  
Hisao Kurazono ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Transcription Factor ◽  
Protein Kinase ◽  
P38 Mapk ◽  
Cyclooxygenase 2 ◽  
Mitogen Activated Protein Kinase ◽  
Mrna Levels ◽  
Mitogen Activated Protein ◽  
Cox 2 ◽  
Activating Transcription Factor

ABSTRACT Treatment of AZ-521 cells with Helicobacter pylori VacA increased cyclooxygenase 2 (COX-2) mRNA in a time- and dose-dependent manner. A p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, blocked elevation of COX-2 mRNA levels, whereas PD98059, which blocks the Erk1/2 cascade, partially suppressed the increase. Consistent with involvement of p38 MAPK, VacA-induced accumulation of COX-2 mRNA was reduced in AZ-521 cells overexpressing a dominant-negative p38 MAPK (DN-p38). Phosphatidylinositol-specific phospholipase C, which inhibits VacA-induced p38 MAPK activation, blocked VacA-induced COX-2 expression. In parallel with COX-2 expression, VacA increased prostaglandin E2 (PGE2) production, which was inhibited by SB203580 and NS-398, a COX-2 inhibitor. VacA-induced PGE2 production was markedly attenuated in AZ-521 cells stably expressing DN-p38. VacA increased transcription of a COX-2 promoter reporter gene and activated a COX-2 promoter containing mutated NF-κB or NF-interleukin-6 sites but not a mutated cis-acting replication element (CRE) site, suggesting direct involvement of the activating transcription factor 2 (ATF-2)/CREB-binding region in VacA-induced COX-2 promoter activation. The reduction of ATF-2 expression in AZ-521 cells transformed with ATF-2-small interfering RNA duplexes resulted in suppression of COX-2 expression. Thus, VacA enhances PGE2 production by AZ-521 cells through induction of COX-2 expression via the p38 MAPK/ATF-2 cascade, leading to activation of the CRE site in the COX-2 promoter.

scholarly journals p38 MAPK α and β isoforms differentially regulate plasma membrane localization of MRP2

2016 ◽  
Vol 310 (11) ◽  
pp. G999-G1005 ◽  
Author(s):  
Christopher M. Schonhoff ◽  
Se Won Park ◽  
Cynthia R.L. Webster ◽  
M. Sawkat Anwer
Keyword(s):  
Plasma Membrane ◽  
P38 Mapk ◽  
Hepatoma Cell ◽  
Sodium Taurocholate ◽  
Mitogen Activated Protein Kinase ◽  
Hepatoma Cell Line ◽  
Mitogen Activated Protein ◽  
P38α Mapk ◽  
Opposing Effects ◽  
Interfering Rna

In hepatocytes, cAMP both activates p38 mitogen-activated protein kinase (MAPK) and increases the amount of multidrug resistance-associated protein-2 (MRP2) in the plasma membrane (PM-MRP2). Paradoxically, taurolithocholate (TLC) activates p38 MAPK but decreases PM-MRP2 in hepatocytes. These opposing effects of cAMP and TLC could be mediated via different p38 MAPK isoforms (α and β) that are activated differentially by upstream kinases (MKK3, MKK4, and MKK6). Thus we tested the hypothesis that p38α MAPK and p38β MAPK mediate increases and decreases in PM-MRP2 by cAMP and TLC, respectively. Studies were conducted in hepatocytes isolated from C57BL/6 wild-type (WT) and MKK3-knockout (MKK3−/−) mice and in a hepatoma cell line (HuH7) that overexpresses sodium-taurocholate cotransporting polypeptide (NTCP) (HuH-NTCP). Cyclic AMP activated MKK3, p38 MAPK, and p38α MAPK and increased PM-MRP2 in WT hepatocytes, but failed to activate p38α MAPK or increase PM-MRP2 in MKK3−/− hepatocytes. In contrast to cAMP, TLC activated total p38 MAPK but decreased PM-MRP2, and did not activate MKK3 or p38α MAPK in WT hepatocytes. In MKK3−/− hepatocytes, TLC still decreased PM-MRP2 and activated p38 MAPK, indicating that these effects are not MKK3-dependent. Additionally, TLC activated MKK6 in MKK3−/− hepatocytes, and small interfering RNA knockdown of p38β MAPK abrogated TLC-mediated decreases in PM-MRP2 in HuH-NTCP cells. Taken together, these results suggest that p38α MAPK facilitates plasma membrane insertion of MRP2 by cAMP, whereas p38β MAPK mediates retrieval of PM-MRP2 by TLC.

scholarly journals Role of MLK3 in the Regulation of Mitogen-Activated Protein Kinase Signaling Cascades

2005 ◽  
Vol 25 (9) ◽  
pp. 3670-3681 ◽  
Author(s):  
Deborah Brancho ◽  
Juan-Jose Ventura ◽  
Anja Jaeschke ◽  
Beth Doran ◽  
Richard A. Flavell ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Map Kinase ◽  
Selective Reduction ◽  
P38 Map Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Signaling Cascades ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Jnk Activation ◽  
Protein Kinase Signaling

ABSTRACT Mixed-lineage protein kinase 3 (MLK3) is a member of the mitogen-activated protein (MAP) kinase kinase kinase group that has been implicated in multiple signaling cascades, including the NF-κB pathway and the extracellular signal-regulated kinase, c-Jun NH2-terminal kinase (JNK), and p38 MAP kinase pathways. Here, we examined the effect of targeted disruption of the murine Mlk3 gene. Mlk3 −/− mice were found to be viable and healthy. Primary embryonic fibroblasts prepared from these mice exhibited no major signaling defects. However, we did find that MLK3 deficiency caused a selective reduction in tumor necrosis factor (TNF)-stimulated JNK activation. Together, these data demonstrate that MLK3 contributes to the TNF signaling pathway that activates JNK.

scholarly journals Molecular mechanisms of neutrophil apoptosis (review)

2018 ◽  
pp. 5-18
Author(s):  
И.А. Щепеткин ◽  
О.П. Буданова ◽  
И.Ю. Малышев ◽  
Д.Н. Аточин
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Mitogen Activated Protein Kinase ◽  
Neutrophil Apoptosis ◽  
Nuclear Factor ◽  
Phosphatidylinositol 3 Kinase ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Nuclear Factor Kb

В обзоре представлены современные данные о механизмах инициации, регуляции и выполнении процесса апоптоза нейтрофилов с участием «рецепторов смерти», митохондрий, белков семейства Bcl-2, PI3-K (phosphatidylinositol 3-kinase), протеинкиназных каскадов p38 MAPK (mitogen-activated protein kinase), ERK (extracellular signal regulated kinase) и JNK (c-Jun N-terminal kinase), протеинкиназ А, В и С, сAMP, белков теплового шока, NF-kB (nuclear factor-kB), кальпаинов, каспаз и их ингибиторов, активных форм кислорода и других факторов. Предложена гипотетическая модель вовлечения апоптотических процессов в регуляцию дифференцировки и реактивности нейтрофилов. This review presented recent data on initiation, regulation, and execution of neutrophil apoptosis with participation of «death receptors», mitochondria, Bcl-2 family proteins, PI3-K (phosphatidylinositol 3-kinase), p38 MAPK (mitogen-activated protein kinase), ERK (extracellular signal regulated kinase) and JNK (c-Jun N-terminal kinase) cascades, protein kinases A, B and C, сAMP, heat shock proteins, NF-kB (nuclear factor-kB), calpains, caspases and theirs inhibitors, reactive oxygen species, and other factors. A speculative model of the apoptotic processes involvement in the regulation of neutrophil differentiation and reactivity was proposed.

scholarly journals Posttranslational Regulation of Tristetraprolin Subcellular Localization and Protein Stability by p38 Mitogen-Activated Protein Kinase and Extracellular Signal-Regulated Kinase Pathways

2006 ◽  
Vol 26 (6) ◽  
pp. 2408-2418 ◽  
Author(s):  
Matthew Brook ◽  
Carmen R. Tchen ◽  
Tomas Santalucia ◽  
Joanne McIlrath ◽  
J. Simon C. Arthur ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Subcellular Localization ◽  
Protein Stability ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Extracellular Signal Regulated Kinase ◽  
P38 Mapk Pathway ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

ABSTRACT The p38 mitogen-activated protein kinase (MAPK) signaling pathway, acting through the downstream kinase MK2, regulates the stability of many proinflammatory mRNAs that contain adenosine/uridine-rich elements (AREs). It is thought to do this by modulating the expression or activity of ARE-binding proteins that regulate mRNA turnover. MK2 phosphorylates the ARE-binding and mRNA-destabilizing protein tristetraprolin (TTP) at serines 52 and 178. Here we show that the p38 MAPK pathway regulates the subcellular localization and stability of TTP protein. A p38 MAPK inhibitor causes rapid dephosphorylation of TTP, relocalization from the cytoplasm to the nucleus, and degradation by the 20S/26S proteasome. Hence, continuous activity of the p38 MAPK pathway is required to maintain the phosphorylation status, cytoplasmic localization, and stability of TTP protein. The regulation of both subcellular localization and protein stability is dependent on MK2 and on the integrity of serines 52 and 178. Furthermore, the extracellular signal-regulated kinase (ERK) pathway synergizes with the p38 MAPK pathway to regulate both stability and localization of TTP. This effect is independent of kinases that are known to be synergistically activated by ERK and p38 MAPK. We present a model for the actions of TTP and the p38 MAPK pathway during distinct phases of the inflammatory response.

Abstract 1172: Neointima Formation is Dependent on p38α Mitogen-Activated Protein Kinase

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Brandon M Proctor ◽  
Anthony J Muslin
Keyword(s):  
P38 Mapk ◽  
Carotid Arteries ◽  
Thymidine Incorporation ◽  
Fold Increase ◽  
Arterial Injury ◽  
Mitogen Activated Protein Kinase ◽  
Neointima Formation ◽  
Mapk Activity ◽  
Mitogen Activated Protein ◽  
P38α Mapk

Neointima formation frequently occurs after arterial injury and is responsible for substantial human morbidity. We previously demonstrated that the intracellular linker protein Grb2 is required for neointima formation, and that Grb2 regulates p38α mitogen-activated protein kinase (MAPK) activation in vascular smooth muscle cells (SMCs). In this work, the role of p38α MAPK in neointima formation was examined. In vitro experiments showed that pharmacological inhibition of p38 MAPK activity in cultured SMCs blocked platelet-derived growth factor (PDGF)-stimulated DNA replication and cell proliferation. Specifically, in control SMCs, overnight stimulation with PDGF induced an 11.8-fold increase in thymidine incorporation and a 1.9 fold increase in cell number. However, inhibition of p38 MAPK activity reduced PDGF-induced thymidine incorporation to 2.8-fold (P = 0.0006) and completely blocked PDGF-stimulated cell proliferation (P = 0.0001). Also, p38 MAPK activity was required for PDGF-induced inactivation of the retinoblastoma tumor suppressor protein, Rb, and induction of mini-chromosome maintenance protein-6 (MCM6), a fundamental regulator of DNA replication. Next, compound transgenic mice were generated with doxycycline (Dox)-inducible, SMC-specific expression of a dominant-negative form of p38α MAPK (SMC-DN-p38α ). Dox induced robust expression of DN-p38α mRNA and protein in the aorta and carotid arteries of compound transgenic mice, and inactivation of native, arterial p38 MAPK. SMC-DN-p38α and single transgenic, control mice were subjected to carotid injury by use of an epoxy resin-beaded probe. After 21 days, control mice developed robust neointima formation that frequently resulted in an occlusive lesion with a mean neointima/media ratio of 2.62 (N = 8). In contrast, SMC-DN-p38α mice were resistant to the development of neointima. Specifically, neointima/media ratio was reduced to 0.63 for SMC-DN-p38α mice (N = 12; P = 0.045). In addition, compared to control mice, injured carotid arteries of SMC-DN-p38α mice showed defective p38 MAPK activation in SMCs of the tunica media. Our results demonstrate that vascular SMC p38α MAPK is required for neointima formation after arterial injury.

Involvement of p38 mitogen–activated protein kinase in different stages of thymocyte development

Blood ◽  
2003 ◽  
Vol 101 (3) ◽  
pp. 970-976 ◽  
Author(s):  
Shu-Ching Hsu ◽  
Chia-Cheng Wu ◽  
Jiahuai Han ◽  
Ming-Zong Lai
Keyword(s):  
T Cell ◽  
Positive Selection ◽  
P38 Mapk ◽  
Cell Receptor ◽  
Dominant Negative ◽  
Mitogen Activated Protein Kinase ◽  
Thymocyte Development ◽  
Dominant Negative Mutation ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

Abstract Positive selection of thymocytes during T-cell development is mediated by T-cell receptor (TCR)–activated signals. For different mitogen-activated protein kinases (MAPKs) activated by TCR complex, a selective involvement of extracellular signal–regulated kinase, but not p38 MAPK, in positive selection has been suggested. Using transgenic mice with dominant-negative mutation of both MAP kinase kinase 3 (MMK3) and MKK6, we obtained mice with different extents of inhibition of p38 MAPK activation. Partial inhibition of p38 MAPK impaired CD4−CD8− thymocyte development and T-cell proliferation, but not positive selection. Interference with thymocyte positive selection was observed in mice with effective suppression of p38 MAPK. Our results suggest that, in addition to early thymocyte development, p38 is involved in positive selection.

Activation of c-Jun N-terminal kinase promotes survival of cardiac myocytes after oxidative stress

2002 ◽  
Vol 362 (3) ◽  
pp. 561-571 ◽  
Author(s):  
Christopher J. DOUGHERTY ◽  
Lori A. KUBASIAK ◽  
Howard PRENTICE ◽  
Peter ANDREKA ◽  
Nanette H. BISHOPRIC ◽  
...  
Keyword(s):  
Cell Fate ◽  
Cardiac Myocytes ◽  
P38 Mapk ◽  
Specific Inhibitor ◽  
Dominant Negative ◽  
Mitogen Activated Protein Kinase ◽  
Jnk Pathway ◽  
Mitogen Activated Protein ◽  
Factor Α ◽  
Jnk Activation

Reperfusion injury occurs when ischaemic tissue is reperfused. It involves the generation and release of reactive oxygen that activates numerous signalling pathways and initiates cell death. Exposure of isolated cardiac myocytes to chronic hypoxia followed by reoxygenation results in the early activation of c-Jun N-terminal kinase (JNK) and death by apoptosis of approx. 30% of the myocytes. Although JNK activation has been described in a number of models of ischaemia/reperfusion, the contribution of JNK activation to cell fate has not been established. Here we report that the activation of JNK by reoxygenation correlates with myocyte survival. Transfection of myocytes with JNK pathway interfering plasmid vectors or infection with adenoviral vectors support the hypothesis that JNK is protective. Transfection or infection with JNK inhibitory mutants increased the rates of apoptosis by almost 2-fold compared with control cultures grown aerobically or subjected to hypoxia and reoxygenation. Caspase 9 activity, measured by LEHD cleavage, increased > 3-fold during reoxygenation and this activity was enhanced significantly at all times in cultures infected with dominant negative JNK adenovirus. Hypoxia—reoxygenation mediated a biphasic (2.6- and 2.9-fold) activation of p38 mitogen-activated protein kinase, as well as a small increase of tumour necrosis factor α (TNFα) secretion, but treatments with the p38 MAPK-specific inhibitor SB203580 or saturating levels of a TNFα-1 blocking antibody provided only partial protection against apoptosis. The results suggest that JNK activation is protective and that the pathway is largely independent of p38 MAPK or secreted TNFα.

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