scholarly journals A Role for the p38 Mitogen-activated Protein Kinase Pathway in Myocardial Cell Growth, Sarcomeric Organization, and Cardiac-specific Gene Expression

1997 ◽  
Vol 139 (1) ◽  
pp. 115-127 ◽  
Author(s):  
Dietmar Zechner ◽  
Donna J. Thuerauf ◽  
Deanna S. Hanford ◽  
Patrick M. McDonough ◽  
Christopher C. Glembotski
Keyword(s):  
Cell Size ◽  
Specific Inhibitor ◽  
Myocardial Cell ◽  
Mitogen Activated Protein Kinase ◽  
Specific Gene ◽  
Hypertrophic Growth ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Upstream Kinase ◽  
Growth Features

Three hallmark features of the cardiac hypertrophic growth program are increases in cell size, sarcomeric organization, and the induction of certain cardiac-specific genes. All three features of hypertrophy are induced in cultured myocardial cells by α1- adrenergic receptor agonists, such as phenylephrine (PE) and other growth factors that activate mitogen- activated protein kinases (MAPKs). In this study the MAPK family members extracellular signal–regulated kinase (ERK), c-jun NH2-terminal kinase (JNK), and p38 were activated by transfecting cultured cardiac myocytes with constructs encoding the appropriate kinases possessing gain-of-function mutations. Transfected cells were then analyzed for changes in cell size, sarcomeric organization, and induction of the genes for the A- and B-type natriuretic peptides (NPs), as well as the α-skeletal actin (α-SkA) gene. While activation of JNK and/or ERK with MEKK1COOH or Raf-1 BXB, respectively, augmented cell size and effected relatively modest increases in NP and α-SkA promoter activities, neither upstream kinase conferred sarcomeric organization. However, transfection with MKK6 (Glu), which specifically activated p38, augmented cell size, induced NP and α-Ska promoter activities by up to 130-fold, and elicited sarcomeric organization in a manner similar to PE. Moreover, all three growth features induced by MKK6 (Glu) or PE were blocked with the p38-specific inhibitor, SB 203580. These results demonstrate novel and potentially central roles for MKK6 and p38 in the regulation of myocardial cell hypertrophy.

scholarly journals Anthrax Lethal Toxin Impairs CD1d-Mediated Antigen Presentation by Targeting the Extracellular Signal-Related Kinase 1/2 Mitogen-Activated Protein Kinase Pathway

2010 ◽  
Vol 78 (5) ◽  
pp. 1859-1863 ◽  
Author(s):  
Masood A. Khan ◽  
Richard M. Gallo ◽  
Randy R. Brutkiewicz
Keyword(s):  
Immune System ◽  
Protein Kinase ◽  
Bacillus Anthracis ◽  
Antigen Presentation ◽  
Specific Inhibitor ◽  
Lethal Toxin ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

ABSTRACT Lethal toxin (LT) is a critical virulence factor of Bacillus anthracis and an important means by which this bacterium evades the host's immune system. In this study, we demonstrate that CD1d-expressing cells treated with LT have reduced CD1d-mediated antigen presentation. We earlier showed an important role for the mitogen-activated protein kinase extracellular signal-regulated kinase 1/2 (ERK1/2) in the regulation of CD1d-mediated antigen presentation, and we report here that LT impairs antigen presentation by CD1d in an ERK1/2-dependent manner. Similarly, LT and the ERK1/2 pathway-specific inhibitor U0126 caused a decrease in major histocompatibility complex (MHC) class II-mediated antigen presentation. Confocal microscopy analyses revealed altered intracellular distribution of CD1d and LAMP-1 in LT-treated cells, similar to the case for ERK1/2-inhibited cells. These results suggest that Bacillus anthracis has the ability to evade the host's innate immune system by reducing CD1d-mediated antigen presentation through targeting the ERK1/2 pathway.

PKC-ε regulation of extracellular signal-regulated kinase: a potential role in phenylephrine-induced cardiocyte growth

2004 ◽  
Vol 286 (6) ◽  
pp. H2195-H2203 ◽  
Author(s):  
Vijay U. Rao ◽  
Hirokazu Shiraishi ◽  
Paul J. McDermott
Keyword(s):  
Growth Regulation ◽  
Dominant Negative ◽  
Mitogen Activated Protein Kinase ◽  
Neonatal Rat ◽  
Inhibitory Effects ◽  
Hypertrophic Growth ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Acute Increase

Hypertrophic growth of cardiac muscle is dependent on activation of the PKC-ε isoform. To define the effectors of PKC-ε involved in growth regulation, recombinant adenoviruses were used to overexpress either wild-type PKC-ε (PKC-ε/WT) or dominant negative PKC-ε (PKC-ε/DN) in neonatal rat cardiocytes. PKC-ε/DN inhibited acute activation of PKC-ε produced in response to phorbol ester and reduced ERK1/2 activity as measured by the phosphorylation of p42 and p44 isoforms. The inhibitory effects were specific to PKC-ε because PKC-ε/DN did not prevent translocation of either PKC-α or PKC-δ. Overexpression of PKC-ε/DN blunted the acute increase in ERK1/2 phorphorylation induced by the α1-adrenergic agonist phenylephrine (PE ). Inhibition of PKC-δ with rottlerin potentiated the effects of PE on ERK1/2 phosphorylation. PKC-ε/DN adenovirus also blocked cardiocyte growth as measured after 48 h of PE treatment, although the multiplicity of infection was lower than that required to block acute ERK1/2 activation. PE activated p38 mitogen-activated protein kinase as measured by its phosphorylation, but the response was not blocked by PKC inhibitors or by overexpression of PKC-ε/DN. Taken together, these studies show that the hypertrophic agonist PE regulates ERK1/2 activity in cardiocytes by a pathway dependent on PKC-ε and that PE-induced growth is mediated by PKC-ε.

Constitutive activation of the MAPK pathway mediates v-fes–induced mitogenesis in murine macrophages

Blood ◽  
2000 ◽  
Vol 95 (12) ◽  
pp. 3959-3963 ◽  
Author(s):  
Elisabetta Rovida ◽  
Fabio Marra ◽  
Manuela Baccarini ◽  
Persio Dello Sbarba
Keyword(s):  
Mapk Pathway ◽  
Specific Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Nonreceptor Tyrosine Kinase ◽  
Murine Macrophages ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Infected Cells ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony

Abstract Fes is a nonreceptor tyrosine kinase expressed at the highest level in macrophages. We previously showed that the overexpression of c-fes in murine macrophages of the BAC-1.2F5 cell line renders these cells independent of macrophage colony-stimulating factor (MCSF) for survival and proliferation, although no direct relationship could be established between tyrosine-phosphorylated substrates of Fes- and MCSF receptor–dependent signaling and mitogenesis. In this study, we investigated whether the mitogen-activated protein kinase (MAPK) pathway is involved in the growth factor–independent growth of v-fes–overexpressing macrophages. We found a constitutively increased phosphorylation of extracellularly regulated kinase (ERK) in v-fes–overexpressing macrophages as compared with mock-infected cells. This finding was associated with activation of mitogen/extracellular signal–regulated kinase (MEK) and with constitutive localization of ERK in the nucleus. Treatment of v-fes–overexpressing cells with the MEK-specific inhibitor PD98059 markedly reduced cell growth, hyperphosphorylation, and nuclear localization of ERK, indicating that the MAPK pathway mediates the mitogenic effect of v-fes.

scholarly journals Mitogen-activated protein kinase translocates to the nucleus during ischaemia and is activated during reperfusion

1997 ◽  
Vol 323 (3) ◽  
pp. 785-790 ◽  
Author(s):  
Yoichi MIZUKAMI ◽  
Ken-ichi YOSHIDA
Keyword(s):  
Map Kinase ◽  
Tyrosine Phosphorylation ◽  
Mitogen Activated Protein Kinase ◽  
Nuclear Fraction ◽  
Cytosol Fraction ◽  
Extracellular Signal ◽  
Ischaemia And Reperfusion ◽  
Mitogen Activated Protein ◽  
Upstream Kinase ◽  
Cellular Stresses

Growth factors and various cellular stresses are known to activate mitogen-activated protein (MAP) kinase, which plays a role in conveying signals from the cytosol to the nucleus. The phosphorylation of MAP kinase is thought to be a prerequisite for translocation. Here, we investigate the translocation and activation of MAP kinase during ischaemia and reperfusion in perfused rat heart. Ischaemia (0–40 min) induces the translocation of MAP kinase from the cytosol fraction to the nuclear fraction. Immunohistochemical observation shows that MAP kinase staining in the nucleus is enhanced after ischaemia for 40 min. Unexpectedly, tyrosine phosphorylation of MAP kinase is unchanged in the nuclear fraction during ischaemia, indicating that unphosphorylated MAP kinase translocates from the cytosol to the nucleus. During reperfusion (0–30 min), after ischaemia for 20 min, tyrosine phosphorylation of MAP kinase in the nuclear fraction is increased with a peak at 10 min of reperfusion. The activation is confirmed by MAP kinase activity with similar kinetics to the tyrosine phosphorylation. However, the amount of MAP kinase in the fraction is almost constant during reperfusion for 10 min. Although an upstream kinase for MAP kinase, MAP kinase/extracellular signal-regulated kinase kinase (MEK)-1, remains in the cytosol throughout ischaemia and reperfusion, MEK-2, another upstream kinase for MAP kinase, is constantly present in the nucleus as well as in the cytoplasm, based on analyses by fractionation and immunohistochemistry. Furthermore, MEK-2 activity in the nuclear fraction is rapidly increased during post-ischaemic reperfusion. These findings demonstrate that nuclear MAP kinase is activated by tyrosine phosphorylation during reperfusion, probably by MEK-2.

scholarly journals The MEK1/2-inhibitor ATR-002 efficiently blocks SARS-CoV-2 propagation and alleviates pro-inflammatory cytokine/chemokine responses

2022 ◽  
Vol 79 (1) ◽  
Author(s):  
André Schreiber ◽  
Dorothee Viemann ◽  
Jennifer Schöning ◽  
Sebastian Schloer ◽  
Angeles Mecate Zambrano ◽  
...  
Keyword(s):  
Drug Evaluation ◽  
Specific Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Erk Signaling ◽  
Selective Treatment ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Culture Models ◽  
Risk Patients ◽  
Novel Coronavirus

AbstractCoronavirus disease 2019 (COVID-19), the illness caused by a novel coronavirus now called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to more than 260 million confirmed infections and 5 million deaths to date. While vaccination is a powerful tool to control pandemic spread, medication to relieve COVID-19-associated symptoms and alleviate disease progression especially in high-risk patients is still lacking. In this study, we explore the suitability of the rapid accelerated fibrosarcoma/mitogen-activated protein kinase/extracellular signal-regulated kinase (Raf/MEK/ERK) pathway as a druggable target in the treatment of SARS-CoV-2 infections. We find that SARS-CoV-2 transiently activates Raf/MEK/ERK signaling in the very early infection phase and that ERK1/2 knockdown limits virus replication in cell culture models. We demonstrate that ATR-002, a specific inhibitor of the upstream MEK1/2 kinases which is currently evaluated in clinical trials as an anti-influenza drug, displays strong anti-SARS-CoV-2 activity in cell lines as well as in primary air–liquid-interphase epithelial cell (ALI) cultures, with a safe and selective treatment window. We also observe that ATR-002 treatment impairs the SARS-CoV-2-induced expression of pro-inflammatory cytokines, and thus might prevent COVID-19-associated hyperinflammation, a key player in COVID-19 progression. Thus, our data suggest that the Raf/MEK/ERK signaling cascade may represent a target for therapeutic intervention strategies against SARS-CoV-2 infections and that ATR-002 is a promising candidate for further drug evaluation.

scholarly journals GIT1 Functions as a Scaffold for MEK1-Extracellular Signal-Regulated Kinase 1 and 2 Activation by Angiotensin II and Epidermal Growth Factor

2004 ◽  
Vol 24 (2) ◽  
pp. 875-885 ◽  
Author(s):  
Guoyong Yin ◽  
Judith Haendeler ◽  
Chen Yan ◽  
Bradford C. Berk
Keyword(s):  
Angiotensin Ii ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Coiled Coil ◽  
Mitogen Activated Protein Kinase ◽  
Interacting Protein ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Upstream Kinase ◽  
Epidermal Growth

ABSTRACT Activation of the mitogen-activated protein kinase pathway represented by extracellular signal-regulated kinases (ERK1/2) and activation of the upstream kinase (MEK1) are critical events for growth factor signal transduction. c-Src has been proposed as a common mediator for these signals in response to both G protein-coupled receptors (GPCRs) and tyrosine kinase-coupled receptors (TKRs). Here we show that the GPCR kinase-interacting protein 1 (GIT1) is a substrate for c-Src that associates with MEK1 in vascular smooth-muscle cells and human embryonic kidney 293 cells. GIT1 binding via coiled-coil domains and a Spa2 homology domain is required for sustained activation of MEK1-ERK1/2 after stimulation with angiotensin II and epidermal growth factor. We propose that GIT1 serves as a scaffold protein to facilitate c-Src-dependent activation of MEK1-ERK1/2 in response to both GPCRs and TKRs.

Constitutive activation of the MAPK pathway mediates v-fes–induced mitogenesis in murine macrophages

Blood ◽  
2000 ◽  
Vol 95 (12) ◽  
pp. 3959-3963 ◽  
Author(s):  
Elisabetta Rovida ◽  
Fabio Marra ◽  
Manuela Baccarini ◽  
Persio Dello Sbarba
Keyword(s):  
Mapk Pathway ◽  
Specific Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Nonreceptor Tyrosine Kinase ◽  
Murine Macrophages ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Infected Cells ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony

Fes is a nonreceptor tyrosine kinase expressed at the highest level in macrophages. We previously showed that the overexpression of c-fes in murine macrophages of the BAC-1.2F5 cell line renders these cells independent of macrophage colony-stimulating factor (MCSF) for survival and proliferation, although no direct relationship could be established between tyrosine-phosphorylated substrates of Fes- and MCSF receptor–dependent signaling and mitogenesis. In this study, we investigated whether the mitogen-activated protein kinase (MAPK) pathway is involved in the growth factor–independent growth of v-fes–overexpressing macrophages. We found a constitutively increased phosphorylation of extracellularly regulated kinase (ERK) in v-fes–overexpressing macrophages as compared with mock-infected cells. This finding was associated with activation of mitogen/extracellular signal–regulated kinase (MEK) and with constitutive localization of ERK in the nucleus. Treatment of v-fes–overexpressing cells with the MEK-specific inhibitor PD98059 markedly reduced cell growth, hyperphosphorylation, and nuclear localization of ERK, indicating that the MAPK pathway mediates the mitogenic effect of v-fes.

scholarly journals Bromamine T (BAT) Exerts Stronger Anti-Cancer Properties than Taurine (Tau)

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 182
Author(s):  
Stella Baliou ◽  
Maria Goulielmaki ◽  
Petros Ioannou ◽  
Christina Cheimonidi ◽  
Ioannis P. Trougakos ◽  
...  
Keyword(s):  
Cytotoxic Effect ◽  
Human Colon ◽  
Mitogen Activated Protein Kinase ◽  
Mitochondrial Apoptosis ◽  
Therapeutic Modalities ◽  
Cancer Pathogenesis ◽  
Extracellular Signal ◽  
Anti Cancer ◽  
Mitogen Activated Protein

Background: Taurine (Tau) ameliorates cancer pathogenesis. Researchers have focused on the functional properties of bromamine T (BAT), a stable active bromine molecule. Both N-bromotaurine (TauNHBr) and BAT exert potent anti-inflammatory properties, but the landscape remains obscure concerning the anti-cancer effect of BAT. Methods: We used Crystal Violet, colony formation, flow cytometry and Western blot experiments to evaluate the effect of BAT and Tau on the apoptosis and autophagy of cancer cells. Xenograft experiments were used to determine the in vivo cytotoxicity of either agent. Results: We demonstrated that both BAT and Tau inhibited the growth of human colon, breast, cervical and skin cancer cell lines. Among them, BAT exerted the greatest cytotoxic effect on both RKO and MDA-MB-468 cells. In particular, BAT increased the phosphorylation of c-Jun N-terminal kinases (JNK½), p38 mitogen-activated protein kinase (MAPK), and extracellular-signal-regulated kinases (ERK½), thereby inducing mitochondrial apoptosis and autophagy in RKO cells. In contrast, Tau exerted its cytotoxic effect by upregulating JNK½ forms, thus triggering mitochondrial apoptosis in RKO cells. Accordingly, colon cancer growth was impaired in vivo. Conclusions: BAT and Tau exerted their anti-tumor properties through the induction of (i) mitochondrial apoptosis, (ii) the MAPK family, and iii) autophagy, providing novel anti-cancer therapeutic modalities.

scholarly journals Identification of the functional components of the Ras signaling pathway regulating pituitary cell-specific gene expression.

1994 ◽  
Vol 14 (3) ◽  
pp. 1553-1565 ◽  
Author(s):  
K E Conrad ◽  
J M Oberwetter ◽  
R Vaillancourt ◽  
G L Johnson ◽  
A Gutierrez-Hartmann
Keyword(s):  
Gene Expression ◽  
Pituitary Cell ◽  
Mitogen Activated Protein Kinase ◽  
Specific Gene ◽  
Ras Signaling ◽  
Raf Kinase ◽  
Prolactin Gene ◽  
Ras Signaling Pathway ◽  
Mitogen Activated Protein ◽  
Prolactin Promoter

Ras, a small GTP-binding protein, is required for functional receptor tyrosine kinase signaling. Ultimately, Ras alters the activity of specific nuclear transcription factors and regulates novel patterns of gene expression. Using a rat prolactin promoter construct in transient transfection experiments, we show that both oncogenic Ras and activated forms of Raf-1 kinase selectively stimulated the cellular rat prolactin promoter in GH4 rat pituitary cells. We also show that the Ras signal is completely blocked by an expression vector encoding a dominant-negative Raf kinase. Additionally, using a molecular genetic approach, we determined that inhibitory forms of p42 mitogen-activated protein kinase and an Ets-2 transcription factor interfere with both the Ras and the Raf activation of the rat prolactin promoter. These findings define a functional requirement for these signaling constituents in the activation of the prolactin gene, a cell-specific gene which marks the lactotroph pituitary cell type. Further, this analysis allowed us to order the components in the Ras signaling pathway as it impinges on regulation of prolactin gene transcription as Ras-->Raf kinase-->mitogen-activated protein kinase-->Ets. In contrast, we show that intact c-Jun expression inhibited the Ras-induced activation of the prolactin promoter, defining it as a negative regulator of this pathway, whereas c-Jun was able to enhance the Ras activation of an AP-1-driven promoter in GH4 cells. These data show that c-Jun is not the nuclear mediator of the Ras signal for the highly specialized, pituitary cell-specific prolactin cellular promoter. Thus, we have defined a model system which provides an ideal paradigm for studying Ras/Raf signaling pathways and their effects on neuroendocrine cell-specific gene regulation.

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