scholarly journals p38 Mitogen-Activated Protein Kinase Is Critical for Synergistic Induction of the FSHβ Gene by Gonadotropin-Releasing Hormone and Activin through Augmentation of c-Fos Induction and Smad Phosphorylation

2007 ◽  
Vol 21 (12) ◽  
pp. 3071-3086 ◽  
Author(s):  
Djurdjica Coss ◽  
Cameron M. Hand ◽  
Karen K. J. Yaphockun ◽  
Heather A. Ely ◽  
Pamela L. Mellon
Keyword(s):  
P38 Mapk ◽  
Dominant Negative ◽  
Mitogen Activated Protein Kinase ◽  
Limiting Factor ◽  
Activator Protein 1 ◽  
Mapk Activity ◽  
C Terminus ◽  
Smad Phosphorylation ◽  
Mitogen Activated Protein ◽  
Smad 3

Abstract GnRH and activin independently and synergistically activate transcription of the FSH β-subunit gene, the subunit that provides specificity and is the limiting factor in the synthesis of the mature hormone. This synergistic interaction, as determined by two-way ANOVA, is specific for FSHβ and may, therefore, contribute to differential expression of the two gonadotropin hormones, which is critical for the reproductive cycle. We find that the cross-talk between the GnRH and activin signaling pathways occurs at the level of p38 MAPK, because the synergy is dependent on p38 MAPK activity, which is activated by GnRH, and activin cotreatment augments p38 activation by GnRH. Both the Smad and activator protein-1 binding sites on the FSHβ promoter are necessary and sufficient for synergy. After cotreatment, Smad 3 proteins are more highly phosphorylated on the activin-receptor signaling-dependent residues on the C terminus than with activin treatment alone, and c-Fos is more highly expressed than with GnRH treatment alone. Inhibition of p38 by either of two different inhibitors or a dominant-negative p38 kinase abrogates synergy on FSHβ expression, reduces c-Fos induction by GnRH, and prevents the further increase in c-Fos levels that occurs with cotreatment. Additionally, p38 is necessary for maximal Smad 3 C-terminal phosphorylation by activin treatment alone and for the further increase caused by cotreatment. Thus, p38 is the pivotal signaling molecule that integrates GnRH and activin interaction on the FSHβ promoter through higher induction of c-Fos and elevated Smad phosphorylation.

Differentiation regulates interleukin-1β-induced cyclo-oxygenase-2 in human articular chondrocytes: role of p38 mitogen-activated protein kinase

2002 ◽  
Vol 362 (2) ◽  
pp. 367-373 ◽  
Author(s):  
Béatrice THOMAS ◽  
Sylvie THIRION ◽  
Lydie HUMBERT ◽  
Lujian TAN ◽  
Mary B. GOLDRING ◽  
...  
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Articular Chondrocytes ◽  
Dominant Negative ◽  
Mitogen Activated Protein Kinase ◽  
Human Articular Chondrocytes ◽  
Osteoarthritic Cartilage ◽  
Mapk Activity ◽  
Mitogen Activated Protein ◽  
Cox 2

Chondrocyte dedifferentiation has been noted in osteoarthritic cartilage, but the contribution of this phenomenon is poorly understood. Interleukin (IL)-1β, the major pro-inflammatory cytokine found in osteoarthritic synovial fluid, induces the dedifferentiation of cultured articular chondrocytes, whereas E-series prostaglandins (PGE) are capable of inducing cell differentiation. Since PGE2 synthesis is up-regulated by IL-1β, we addressed the question of whether the state of chondrocyte differentiation may influence the production of IL-1-induced PGE2 by modulating cyclooxygenase (COX)-2 expression. Immortalized human articular chondrocytes, (tsT/AC62) cultured in monolayer after passage through alginate matrix (alg+) produced 5-fold greater amounts of PGE2 than continuous monolayer cultures (alg-) after stimulation with IL-1β. Moreover, IL-1β induced COX-2 expression at 0.01ng/ml in (alg+) cells, whereas a 100-fold higher dose of cytokine was necessary for stimulation in (alg-) cells. SB203580, a selective p38 mitogen-activated protein kinase (MAPK) inhibitor, completely abolished the IL-1β-induced COX-2 mRNA. Overexpression of p38 MAPK induces a COX-2 reporter, whereas overexpression of dominant negative p38 MAPK represses IL-1β-induced promoter expression. Interestingly, IL-1β-induced p38 MAPK activity was greatly enhanced in (alg+) compared with (alg-) cells. Our results suggest that differentiated articular chondrocytes are highly responsive to IL-1β and that p38 MAPK mediates this response by inducing COX-2 gene expression.

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.

Role of p38 mitogen-activated protein kinase in cardiac myocyte secretion of the inflammatory cytokine TNF-α

2001 ◽  
Vol 280 (5) ◽  
pp. H1970-H1981 ◽  
Author(s):  
Cherry Ballard-Croft ◽  
D. Jean White ◽  
David L. Maass ◽  
Dixie Peters Hybki ◽  
Jureta W. Horton
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Cardiac Myocyte ◽  
Total Body Surface Area ◽  
Mitogen Activated Protein Kinase ◽  
Kinase Assay ◽  
Burn Trauma ◽  
Mapk Activity ◽  
Tnf Α ◽  
Mitogen Activated Protein

This study examined the hypothesis that burn trauma promotes cardiac myocyte secretion of inflammatory cytokines such as tumor necrosis factor (TNF)-α and produces cardiac contractile dysfunction via the p38 mitogen-activated protein kinase (MAPK) pathway. Sprague-Dawley rats were divided into four groups: 1) sham burn rats given anesthesia alone, 2) sham burn rats given the p38 MAPK inhibitor SB203580 (6 mg/kg po, 15 min; 6- and 22-h postburn), 3) rats given third-degree burns over 40% total body surface area and treated with vehicle (1 ml of saline) plus lactated Ringer solution for resuscitation (4 ml · kg−1 · percent burn−1), and 4) burn rats given injury and fluid resuscitation plus SB203580. Rats from each group were killed at several times postburn to examine p38 MAPK activity (by Western blot analysis or in vitro kinase assay); myocardial function and myocyte secretion of TNF-α were examined at 24-h postburn. These studies showed significant activation of p38 MAPK at 1-, 2-, and 4-h postburn compared with time-matched shams. Burn trauma impaired cardiac mechanical performance and promoted myocyte secretion of TNF-α. SB203580 inhibited p38 MAPK activity, reduced myocyte secretion of TNF-α, and prevented burn-mediated cardiac deficits. These data suggest p38 MAPK activation is one aspect of the signaling cascade that culminates in postburn secretion of TNF-α and contributes to postburn cardiac dysfunction.

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 p38δMAPK: Emerging Roles of a Neglected Isoform

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Carol O’Callaghan ◽  
Liam J. Fanning ◽  
Orla P. Barry
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Molecular Mechanisms ◽  
Mitogen Activated Protein Kinase ◽  
Biological Processes ◽  
Cellular Processes ◽  
Mapk Activity ◽  
Pathological Conditions ◽  
Mapk Signalling ◽  
Mitogen Activated Protein

p38δmitogen activated protein kinase (MAPK) is a unique stress responsive protein kinase. While the p38 MAPK family as a whole has been implicated in a wide variety of biological processes, a specific role for p38δMAPK in cellular signalling and its contribution to both physiological and pathological conditions are presently lacking. Recent emerging evidence, however, provides some insights into specific p38δMAPK signalling. Importantly, these studies have helped to highlight functional similarities as well as differences between p38δMAPK and the other members of the p38 MAPK family of kinases. In this review we discuss the current understanding of the molecular mechanisms underlying p38δMAPK activity. We outline a role for p38δMAPK in important cellular processes such as differentiation and apoptosis as well as pathological conditions such as neurodegenerative disorders, diabetes, and inflammatory disease. Interestingly, disparate roles for p38δMAPK in tumour development have also recently been reported. Thus, we consider evidence which characterises p38δMAPK as both a tumour promoter and a tumour suppressor. In summary, while our knowledge of p38δMAPK has progressed somewhat since its identification in 1997, our understanding of this particular isoform in many cellular processes still strikingly lags behind that of its counterparts.

scholarly journals Distinct Cellular Functions of MK2

2002 ◽  
Vol 22 (13) ◽  
pp. 4827-4835 ◽  
Author(s):  
Alexey Kotlyarov ◽  
Yvonne Yannoni ◽  
Susann Fritz ◽  
Kathrin Laaß ◽  
Jean-Baptiste Telliez ◽  
...  
Keyword(s):  
Cell Migration ◽  
Catalytic Activity ◽  
Protein Kinase ◽  
P38 Mapk ◽  
Mitogen Activated Protein Kinase ◽  
Cellular Functions ◽  
Protein Levels ◽  
C Terminus ◽  
Mitogen Activated Protein ◽  
Migratory Phenotype

ABSTRACT Mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2) is activated upon stress by p38 MAPKα and -β, which bind to a basic docking motif in the C terminus of MK2 and which subsequently phosphorylate its regulatory sites. As a result of activation MK2 is exported from the nucleus to the cytoplasm and cotransports active p38 MAPK to this compartment. Here we show that the amount of p38 MAPK is significantly reduced in cells and tissues lacking MK2, indicating a stabilizing effect of MK2 for p38. Using a murine knockout model, we have previously shown that elimination of MK2 leads to a dramatic reduction of tumor necrosis factor (TNF) production in response to lipopolysaccharide. To further elucidate the role of MK2 in p38 MAPK stabilization and in TNF biosynthesis, we analyzed the ability of two MK2 isoforms and several MK2 mutants to restore both p38 MAPK protein levels and TNF biosynthesis in macrophages. We show that MK2 stabilizes p38 MAPK through its C terminus and that MK2 catalytic activity does not contribute to this stabilization. Importantly, we demonstrate that stabilizing p38 MAPK does not restore TNF biosynthesis. TNF biosynthesis is only restored with MK2 catalytic activity. We further show that, in MK2-deficient macrophages, formation of filopodia in response to extracellular stimuli is reduced. In addition, migration of MK2-deficient mouse embryonic fibroblasts (MEFs) and smooth muscle cells on fibronectin is dramatically reduced. Interestingly, reintroducing catalytic MK2 activity into MEFs alone is not sufficient to revert the migratory phenotype of these cells. In addition to catalytic activity, the proline-rich N-terminal region is necessary for rescuing the migratory phenotype. These data indicate that catalytic activity of MK2 is required for both cytokine production and cell migration. However, the proline-rich MK2 N terminus provides a distinct role restricted to cell migration.

Lyn tyrosine kinase regulates thrombopoietin-induced proliferation of hematopoietic cell lines and primary megakaryocytic progenitors

Blood ◽  
2004 ◽  
Vol 103 (10) ◽  
pp. 3736-3743 ◽  
Author(s):  
Brian J. Lannutti ◽  
Jonathan G. Drachman
Keyword(s):  
Cellular Proliferation ◽  
Kinase Inhibitors ◽  
Dominant Negative ◽  
Janus Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Activity ◽  
Targeted Mutation ◽  
Mitogen Activated Protein ◽  
Nuclear Ploidy

Abstract In this study we demonstrate that thrombopoietin (TPO)–stimulated Src family kinases (SFKs) inhibit cellular proliferation and megakaryocyte differentiation. Using the Src kinase inhibitors pyrolopyrimidine 1 and 2 (PP1, PP2), we show that TPO-dependent proliferation of BaF3/Mpl cells was enhanced at concentrations that are specific for SFKs. Similarly, proliferation is increased after introducing a dominant-negative form of Lyn into BaF3/Mpl cells. Murine marrow cells from Lyn-deficient mice or wild-type mice cultured in the presence of the Src inhibitor, PP1, yielded a greater number of mature megakaryocytes and increased nuclear ploidy. Truncation and targeted mutation of the Mpl cytoplasmic domain indicate that Y112 is critical for Lyn activation. Examining the molecular mechanism for this antiproliferative effect, we determined that SFK inhibitors did not affect tyrosine phosphorylation of Janus kinase 2 (JAK2), Shc, signal transducer and activator of transcription (STAT)5, or STAT3. In contrast, pretreatment of cells with PP2 increased Erk1/2 (mitogen-activated protein kinase [MAPK]) phosphorylation and in vitro kinase activity, particularly after prolonged TPO stimulation. Taken together, our results show that Mpl stimulation results in the activation of Lyn kinase, which appears to limit the proliferative response through a signaling cascade that regulates MAPK activity. These data suggest that SFKs modify the rate of TPO-induced proliferation and are likely to affect cell cycle regulation during megakaryocytopoiesis.

scholarly journals Trophic Factor Withdrawal: p38 Mitogen-Activated Protein Kinase Activates NHE1, Which Induces Intracellular Alkalinization

2001 ◽  
Vol 21 (22) ◽  
pp. 7545-7557 ◽  
Author(s):  
Annette R. Khaled ◽  
Andrea N. Moor ◽  
Aiqun Li ◽  
Kyungjae Kim ◽  
Douglas K. Ferris ◽  
...  
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
Dominant Negative ◽  
Mitogen Activated Protein Kinase ◽  
Trophic Factor ◽  
Cytokine Signaling ◽  
Amino Acid Region ◽  
Mitogen Activated Protein ◽  
Intracellular Alkalinization

ABSTRACT Trophic factor withdrawal induces cell death by mechanisms that are incompletely understood. Previously we reported that withdrawal of interleukin-7 (IL-7) or IL-3 produced a rapid intracellular alkalinization, disrupting mitochondrial metabolism and activating the death protein Bax. We now observe that this novel alkalinization pathway is mediated by the pH regulator NHE1, as shown by the requirement for sodium, blocking by pharmacological inhibitors or use of an NHE1-deficient cell line, and the altered phosphorylation of NHE1. Alkalinization also required the stress-activated p38 mitogen-activated protein kinase (MAPK). Inhibition of p38 MAPK activity with pharmacological inhibitors or expression of a dominant negative kinase prevented alkalinization. Activated p38 MAPK directly phosphorylated the C terminus of NHE1 within a 40-amino-acid region. Analysis by mass spectroscopy identified four phosphorylation sites on NHE1, Thr 717, Ser 722, Ser 725, and Ser 728. Thus, loss of trophic cytokine signaling induced the p38 MAPK pathway, which phosphorylated NHE1 at specific sites, inducing intracellular alkalinization.

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