scholarly journals SRC family kinase (SFK) inhibition reduces rhabdomyosarcoma cell growth in vitro and in vivo and triggers p38 MAP kinase-mediated differentiation

Oncotarget ◽  
2015 ◽  
Vol 6 (14) ◽  
pp. 12421-12435 ◽  
Author(s):  
Nadia Casini ◽  
Iris Maria Forte ◽  
Gianmarco Mastrogiovanni ◽  
Francesca Pentimalli ◽  
Adriano Angelucci ◽  
...  
Keyword(s):  
Cell Growth ◽  
Map Kinase ◽  
P38 Map Kinase ◽  
Src Family Kinase ◽  
Rhabdomyosarcoma Cell

Evidence for modulation of smooth muscle force by the p38 MAP kinase/HSP27 pathway

2000 ◽  
Vol 278 (6) ◽  
pp. H1899-H1907 ◽  
Author(s):  
Ilia A. Yamboliev ◽  
Jason C. Hedges ◽  
Jack L.-M. Mutnick ◽  
Leonard P. Adam ◽  
William T. Gerthoffer
Keyword(s):  
Smooth Muscle ◽  
Muscle Contraction ◽  
Map Kinase ◽  
Map Kinases ◽  
Contractile Response ◽  
P38 Map Kinase ◽  
Hsp27 Phosphorylation ◽  
Sb 203580

Mitogen-activated protein (MAP) kinases signal to proteins that could modify smooth muscle contraction. Caldesmon is a substrate for extracellular signal-related kinases (ERK) and p38 MAP kinases in vitro and has been suggested to modulate actin-myosin interaction and contraction. Heat shock protein 27 (HSP27) is downstream of p38 MAP kinases presumably participating in the sustained phase of muscle contraction. We tested the role of caldesmon and HSP27 phosphorylation in the contractile response of vascular smooth muscle by using inhibitors of both MAP kinase pathways. In intact smooth muscle, PD-098059 abolished endothelin-1 (ET-1)-stimulated phosphorylation of ERK MAP kinases and caldesmon, but p38 MAP kinase activation and contractile response remained unaffected. SB-203580 reduced muscle contraction and inhibited p38 MAP kinase and HSP27 phosphorylation but had no effect on ERK MAP kinase and caldesmon phosphorylation. In permeabilized muscle fibers, SB-203580 and a polyclonal anti-HSP27 antibody attenuated ET-1-dependent contraction, whereas PD-098059 had no effect. These results suggest that ERK MAP kinases phosphorylate caldesmon in vivo but that activation of this pathway is unnecessary for force development. The generation of maximal force may be modulated by the p38 MAP kinase/HSP27 pathway.

scholarly journals Dual Blockade of the PI3K/AKT/mTOR (AZD8055) and RAS/MEK/ERK (AZD6244) Pathways Synergistically Inhibits Rhabdomyosarcoma Cell Growth In Vitro and In Vivo

2013 ◽  
Vol 19 (21) ◽  
pp. 5940-5951 ◽  
Author(s):  
Jane Renshaw ◽  
Kathryn R. Taylor ◽  
Ryan Bishop ◽  
Melanie Valenti ◽  
Alexis De Haven Brandon ◽  
...  
Keyword(s):  
Cell Growth ◽  
Rhabdomyosarcoma Cell ◽  
Dual Blockade

scholarly journals Selective Inhibition of the Myeloid Src-Family Kinase Fgr Potently Suppresses AML Cell Growth in Vitro and in Vivo

2018 ◽  
Vol 13 (6) ◽  
pp. 1551-1559 ◽  
Author(s):  
Mark C. Weir ◽  
Sherry T. Shu ◽  
Ravi K. Patel ◽  
Sabine Hellwig ◽  
Li Chen ◽  
...  
Keyword(s):  
Cell Growth ◽  
Selective Inhibition ◽  
Src Family Kinase

Src-family kinase signaling modulates the adhesion ofPlasmodium falciparum on human microvascular endothelium under flow

Blood ◽  
2003 ◽  
Vol 101 (7) ◽  
pp. 2850-2857 ◽  
Author(s):  
Bryan G. Yipp ◽  
Stephen M. Robbins ◽  
Mary E. Resek ◽  
Dror I. Baruch ◽  
Sornchai Looareesuwan ◽  
...  
Keyword(s):  
Alkaline Phosphatase ◽  
Map Kinase ◽  
Intracellular Signaling ◽  
Kinase Activity ◽  
Flow Chamber ◽  
P38 Map Kinase ◽  
Src Family Kinase ◽  
Microvascular Endothelium ◽  
Recombinant Peptide

The pathogenicity of Plasmodium falciparum is due to the unique ability of infected erythrocytes (IRBCs) to adhere to vascular endothelium. We investigated whether adhesion of IRBCs to CD36, the major cytoadherence receptor on human dermal microvascular endothelial cells (HDMECs), induces intracellular signaling and regulates adhesion. A recombinant peptide corresponding to the minimal CD36-binding domain from P falciparum erythrocyte membrane protein 1 (PfEMP1), as well as an anti-CD36 monoclonal antibody (mAb) that inhibits IRBC binding, activated the mitogen-activated protein (MAP) kinase pathway that was dependent on Src-family kinase activity. Treatment of HDMECs with a Src-family kinase–selective inhibitor (PP1) inhibited adhesion of IRBCs in a flow-chamber assay by 72% (P < .001). More importantly, Src-family kinase activity was also required for cytoadherence to intact human microvessels in a human/severe combined immunodeficient (SCID) mouse model in vivo. The effect of PP1 could be mimicked by levamisole, a specific alkaline-phosphatase inhibitor. Firm adhesion to PP1-treated endothelium was restored by exogenous alkaline phosphatase. In contrast, inhibition of the extracellular signal–regulated kinase 1/2 (ERK 1/2) and p38 MAP kinase pathways had no immediate effect on IRBC adhesion. These results suggest a novel mechanism for the modulation of cytoadherence under flow conditions through a signaling pathway involving CD36, Src-family kinases, and an ectoalkaline phosphatase. Targeting endothelial ectoalkaline phosphatases and/or signaling molecules may constitute a novel therapeutic strategy against severe falciparum malaria.

p38 alpha MAP Kinase Inhibitor Inhibits Human Myeloma Cell Growth in Vivo.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4936-4936
Author(s):  
Mamatha Reddy ◽  
Jing Y. Ma ◽  
Irene Kerr ◽  
Nirupama Henjarappa ◽  
Tony Navas ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Growth ◽  
Map Kinase ◽  
Tumor Size ◽  
Tumor Volume ◽  
Myeloma Cell ◽  
P38 Map Kinase ◽  
P38 Inhibitor ◽  
Human Myeloma Cell

Abstract The p38 MAPK signaling pathway plays an important role in different pathological conditions and specific inhibitors of p38 alpha and beta MAPK block production of major inflammatory cytokines. Human multiple myeloma (MM) is an incurable neoplasm of B cells, and MM disease progression is affected by immunoregulatory elements such as IL-6 and other cytokines. Recent literature indicates that an important function of p38 MAP kinase is the generation of signals of critical value to the control of normal and malignant hematopoiesis by cytokines and growth factors. We therefore examined the effect of a p38 alpha MAP kinase specific inhibitor, SD-282, on human myeloma cell (RPMI8266) tumor growth in immunodeficient beige-nude-xid mouse xenograft plasmacytoma model. Treatment (90 mg/kg/bid by oral gavage) was initiated in mice with palpable tumor size (~200 mm3) as judged by tumor volume. In mice with palpable tumors, 21 days of SD-282 treatment significantly reduced tumor volume. When SD-282 treatment was initiated in mice with pronounced tumor size (~800 mm3) there remained a significant reduction in tumor volume. Histological assessment at the end of dosing from animals administered SD-282 or vehicle demonstrated a significant reduction in tumor volume and number of neoformed microvessels in the SD-282 treatment group. It also significantly reduced HSP27 and p38 expressions in tumor cells. In conclusion, we report that the p38 inhibitor inhibits human myeloma cell growth in vivo via p38 MAP kinase signaling pathway. The current study provides strong in vivo evidence supporting use of p38 inhibitor therapy in patients with multiple myeloma

scholarly journals MAP Kinase Kinase 6–p38 MAP Kinase Signaling Cascade Regulates Cyclooxygenase-2 Expression in Cardiac Myocytes In Vitro and In Vivo

2003 ◽  
Vol 92 (7) ◽  
pp. 757-764 ◽  
Author(s):  
Norbert Degousee ◽  
Joshua Martindale ◽  
Eva Stefanski ◽  
Martin Cieslak ◽  
Thomas F. Lindsay ◽  
...  
Keyword(s):  
Map Kinase ◽  
Cardiac Myocytes ◽  
P38 Map Kinase ◽  
Cyclooxygenase 2 ◽  
Signaling Cascade ◽  
Kinase Signaling ◽  
Map Kinase Signaling ◽  
Map Kinase Kinase

scholarly journals Differential Activation of Mitogen-Activated Protein Kinases in Experimental Mesangioproliferative Glomerulonephritis

2000 ◽  
Vol 11 (2) ◽  
pp. 232-240
Author(s):  
DIRK BOKEMEYER ◽  
TAMMO OSTENDORF ◽  
UTA KUNTER ◽  
MARION LINDEMANN ◽  
HERBERT J. KRAMER ◽  
...  
Keyword(s):  
Map Kinase ◽  
Map Kinases ◽  
Cellular Proliferation ◽  
Kinase Activity ◽  
P38 Map Kinase ◽  
Cellular Growth ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Maximal Increase

Abstract. Multiple extracellular mitogens are involved in the pathogenesis of proliferative forms of glomerulonephritis (GN). In vitro studies demonstrate the pivotal role of mitogenactivated protein (MAP) kinases in the regulation of cellular proliferation. This study was conducted to examine whether these kinases, as a convergence point of mitogenic stimuli, are activated in mesangioproliferative GN in vivo. Therefore, anti-Thy1 GN was induced in rats using a monoclonal anti-Thy1.1 antibody (OX-7). Whole cortical tissue as well as isolated glomeruli were examined at different time points using kinase activity assays and Western blot analysis. A maximal increase in the number of glomerular mitotic figures (9.7-fold) was demonstrated 6 d after injection of the anti-Thy1.1 antibody. In parallel with this finding, a significant increase in cortical, and more dramatically glomerular, activity of extracellular signal-regulated kinase (ERK) was detected. Maximal activation of ERK was detectable on day 6. This activation of ERK was accompanied by an increase in the expression of MEK (MAP kinase/ERK kinase), the ERK-activating kinase. A marked induction of glomerular apoptosis at 2 h after injection of the anti-Thy1.1 antibody, which subsided subsequently, was demonstrated using the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay as well as staining for single-stranded DNA. However, no significant activation of stress-activated protein kinase or p38 MAP kinase, both MAP kinases that are suggested to induce apoptosis and to inhibit cellular growth, was detectable at this early time point. Rather, on day 6 a dramatic decrease in the activity of p38 MAP kinase, which might have contributed to the overshooting glomerular cellular proliferation, was observed. Treatment of rats with heparin blunted glomerular proliferation as well as ERK activation and restored p38 MAP kinase activity. These observations point to ERK and p38 MAP kinase as putative mediators of the proliferative response in mesangioproliferative GN and suggest that upregulation of MEK is involved in the long-term regulation of ERK in vivo.

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