Search results for "MAPK"
showing 10 items of 238 documents
Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascade inhibitors: How mutations can result in therapy resistance and how to overcome resistance
2012
// James A. McCubrey 1 , Linda S. Steelman 1 , William H. Chappell 1 , Stephen L. Abrams 1 , Richard A. Franklin 1 , Giuseppe Montalto 2 , Melchiorre Cervello 3 , Massimo Libra 4 , Saverio Candido 4 , Grazia Malaponte 4 , Maria C. Mazzarino 4 , Paolo Fagone 4 , Ferdinando Nicoletti 4 , Jorg Basecke 5 , Sanja Mijatovic 6 , Danijela Maksimovic-Ivanic 6 , Michele Milella 7 , Agostino Tafuri 8 , Francesca Chiarini 9 , Camilla Evangelisti 9 , Lucio Cocco 10 , Alberto M. Martelli 9,10 1 Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA 2 Department of Internal Medicine and Specialties, University of Palermo, Palermo, Italy 3 Consi…
Activation of MAP kinase signaling pathway in the mussel Mytilus galloprovincialis as biomarker of environmental pollution
2010
Stimulation of MAP kinase signal transduction pathway by various stressful stimuli was investigated in the marine bivalve Mytilus galloprovincialis. Analyses were performed in animals exposed in laboratory to selected pollutants and in mussels collected in winter and summer along the eastern Adriatic coast (Croatia). Effects of oxidative stress, induced by tributyltin, hydrogen peroxide and water soluble fraction of diesel fuel on the activation/phosphorylation of the three Mitogen-Activated Protein Kinases (MAPKs) p38, JNK and ERK using a newly developed ELISA procedure were evaluated. MAP kinase activation was analyzed 1 h after exposure of mussels to chemical agents, and after recovery p…
P38 MAP Kinase Signaling Is Required for the Conversion of CD4+CD25− T Cells into iTreg
2008
CD4+CD25+ regulatory T cells (Treg) are important mediators of immune tolerance. A subset of Treg can be generated in the periphery by TGF-beta dependent conversion of conventional CD4+CD25− T cells into induced Treg (iTreg). In chronic viral infection or malignancy, such induced iTreg, which limit the depletion of aberrant or infected cells, may be of pathogenic relevance. To identify potential targets for therapeutic intervention, we investigated the TGF-beta signaling in Treg. In contrast to conventional CD4+ T cells, Treg exhibited marked activation of the p38 MAP kinase pathway. Inhibition of p38 MAP kinase activity prevented the TGF-beta-dependent conversion of CD4+CD25− T cells into …
Activation of MAP kinase p38 is critical for the cell-cycle–controlled suppressor function of regulatory T cells
2007
AbstractRegulatory T cells play an essential role in the control of self-tolerance and processes of adaptive immunity. Tolerogenic IL-10–modulated human dendritic cells (IL-10DCs) induce anergic T cells with strong suppressive properties (iTregs) that inhibit the activation of effector T cells. In this study, we evaluated the interaction between cell-cycle regulation and intracellular signaling in these iTregs. Analysis of signal transduction events revealed a down-regulation of the mitogen-activated protein kinases (MAPKs) Jun N-terminal kinase (JNK) and a nonactivation of extracellular-signal–regulated kinase (ERK) in contrast to a marked activation of p38 MAPK and the p38 effector MAPK-a…
Effects of Scrophularia ningpoensis Hemsl. on Inhibition of Proliferation, Apoptosis Induction and NF-κB Signaling of Immortalized and Cancer Cell Li…
2012
Scrophularia ningpoensis has been used in China for centuries as a herbal tea to treat various diseases. Based on the numerous animal studies on its pharmaceutical effects and the long time clinical experiences, we studied the molecular and cellular mechanism underlying the bioactivity of aqueous extract of Scrophularia and its isolated compounds. Seven isolated compounds, unlike Scrophularia extract, failed to induce cytotoxicity on HaCaT cells, but their combination improved the effect of extract. Tumor cell line selectivity was not observed, when we studied its cytotoxic effect on melanoma cell lines. The apoptotic and anti-inflammatory effects of Scrophularia extract have been demonstra…
Evolution of osmosensing signal transduction in Metazoa: stress-activated protein kinases p38 and JNK.
2001
Sponges (Porifera) represent the most basal branch of the Metazoa alive today. We show that two central stress-activated protein kinases involved in the osmosensing pathway, p38 mitogen-activated protein kinase (MAPK) and JNK, can complement for the ancestral MAPK Hog1 in the yeast Saccharomyces cerevisiae. S. cerevisiae mutants lacking Hog1 (hog1-Delta 1) have been complemented with the sponge SDJNK and SDp38 genes. Western blotting has revealed that, after transformation, the hog1-Delta 1+ SDJNK(sense) and hog1-Delta 1+ SDp38(sense) clones express the sponge proteins. Functional studies have demonstrated that the complemented clones grow under hyperosmotic conditions (0.6 M NaCl). Further…
Synergistic Growth Inhibitory Activity of Combined Mek/Mtor Pathway Blockade in Pten-Null Cancers
2014
ABSTRACT Aim: We have recently shown that induction of PTEN expression plays an integral role in MEK inhibitors' antitumor activity. Here we hypothesize that PTEN status critically influences the functional outcome of combined MEK and PI3K/mTOR inhibition. Methods: Single and combined MEK (trametinib, T) and mTOR (everolimus, E) blockade were assessed in a panel of cancer cell lines and in patient-derived lung and colon cancer stem cells (L- or C-CSC). Pharmacologic interactions were analyzed by conservative isobologram analysis. PTEN role was assessed by shRNA-mediated silencing or overexpression by stable transfection. Treatment-induced changes in the phosphoproteome were analyzed by anti…
Molecular mechanisms mediating the neuroprotective role of the selective estrogen receptor modulator, bazedoxifene, in acute ischemic stroke: A compa…
2017
As the knowledge on the estrogenic system in the brain grows, the possibilities to modulate it in order to afford further neuroprotection in brain damaging disorders so do it. We have previously demonstrated the ability of the selective estrogen receptor modulator, bazedoxifene (BZA), to reduce experimental ischemic brain damage. The present study has been designed to gain insight into the molecular mechanisms involved in such a neuroprotective action by investigating: 1) stroke-induced apoptotic cell death; 2) expression of estrogen receptors (ER) ERα, ERβ and the G-protein coupled estrogen receptor (GPER); and 3) modulation of MAPK/ ERK1/2 and PI3K/Akt signaling pathways. For comparison, …
Additive effects of cherlerythrine chloride combination with erlotinib in human non-small cell lung cancer cells
2017
Several studies implicate that lung cancer progression is governed by the interaction between epidermal growth factor receptor (EGFR) signaling and protein kinase C (PKC) pathways. Combined the targeting of EGFR and PKC may have an additive or synergistic effects in lung cancer treatment. The aim of this study is to explore the potential utility by inhibiting these two pathways with the combination of erlotinib and chelerythrine chloride in non-small cell lung cancer (NSCLC) cell lines. The erlotinib-less sensitive cell lines SK-MES-1 and A549 were treated with erlotinib or chelerythrine by themselves or in combination with each other. The cell viability, clonogenic survival, cell migration…
A Phase Ib Dose-Escalation Study of the Safety, Tolerability, and Pharmacokinetics of Cobimetinib and Duligotuzumab in Patients with Previously Treat…
2017
Abstract Lessons Learned Cobimetinib and duligotuzumab were well tolerated as single agents and in combination with other agents. The cobimetinib and duligotuzumab combination was associated with increased toxicity, most notably gastrointestinal, and limited efficacy in the patient population tested. Background KRAS-mutant tumors possess abnormal mitogen-activated protein kinases (MAPK) pathway signaling, leading to dysregulated cell proliferation. Cobimetinib blocks MAPK signaling. The dual-action antibody duligotuzumab (MEHD7945A) inhibits ligand binding to both epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3). Blockade of EGFR/HER3 and inhibitio…