scholarly journals Selective Inhibition of Mitochondrial JNK Signaling Achieved Using Peptide Mimicry of the Sab Kinase Interacting Motif-1 (KIM1)

2011 ◽  
Vol 6 (8) ◽  
pp. 808-818 ◽  
Author(s):  
Jeremy W. Chambers ◽  
Lisa Cherry ◽  
John D. Laughlin ◽  
Mariana Figuera-Losada ◽  
Philip V. LoGrasso
Keyword(s):  
Selective Inhibition ◽  
Jnk Signaling ◽  
Peptide Mimicry

In AML, Cbl Serves as Nexus for Signaling from Flt3, and Is Required for Coupling JNK1 in a Pathway of Survival and Proliferation Involving c-jun/AP-1.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1203-1203
Author(s):  
Amy D. Hartman ◽  
Annique Wilson-Weekes ◽  
Attaya Suvannasankha ◽  
Gem S. Burgess ◽  
Kathryn J. Hincher ◽  
...  
Keyword(s):  
Cell Lines ◽  
Leukemic Cell ◽  
Adaptor Proteins ◽  
Selective Inhibition ◽  
Multidrug Resistant ◽  
Activity Level ◽  
Jnk Signaling ◽  
Leukemic Cell Lines ◽  
Functional Relevance ◽  
Sirna Knockdown

Abstract Here we demonstrate by immunoprecipitation and immunoblot, cbl is among the most heavily tyrosine phosphorylated adaptor proteins in primary AML blasts with Flt3 signaling, in the context of either mutation or overexpression/autocrine mechanisms. The human leukemic cell lines MV-4-11 and THP-1 model primary AML blasts in terms of Flt3 signaling by these respective criteria and demonstrate identical coupling between Flt3 and p85, the PI-3-kinase adaptor, by coimmunoprecipitation/blot experiments. Although cbl has no direct binding site on Flt3, it binds tightly to p85 SH2 by virtue of its tyrosine phosphorylation, also demonstrated by co-IP in cell lines and primary cells. Tyrosine phosphorylated cbl is a docking site for CrkII/L SH2’s and this provides a branch point for signals from Flt3 to PI-3-kinase or JNK, respectively, because CrkII(L) is known to bind JNK1 through SH3: polyproline interaction to serve as scaffolding; and interaction of JNK1 and CrkII/L was also observed by co-IP. In a survey of primary AML cases (n=33) there was a strict relationship between expression levels of (active) Flt3 and phospho-c-jun as readout for JNK activity level (p=0.001, r=0.54). To demonstrate the functional relevance of these interactions, siRNA knockdown of components was pursued in the cell lines and in primary AML blasts. JNK1 knockdown, and, to a much lesser degree, JNK2 knockdown, led to loss of phospho-c-jun expression in MV-4-11 and THP-1. Indeed, Flt3 signaling is required for JNK signaling because knockdown of Flt3 led to total loss of p-jun and c-jun expression in MV-4-11 and patient blast. By contrast, cbl knockdown led to selective loss of JNK signaling to p-jun without significantly affecting Flt3 or its downstream activating phosphorylation of AKT. Thus, despite binding by cbl to p85, cbl is not required for PI-3-kinase signaling because of redundancy supplied by the p85-Flt3 interaction. Further, by use of LY294002 to inhibit PI-3-kinase, PI-3-kinase is also not required for JNK signaling. However, selective inhibition of JNK signaling by the small molecule approach in these cell lines and in primary AML blasts leads to loss of proliferation, induction of apoptosis, and synergistic killing with daunorubicin. These observations form the platform for a phase I trial of JNK inhibition in refractory, multidrug-resistant, and Flt3-driven AML.

Stroma-derived factor 1alpha induces a selective inhibition of human erythroid development via the functional upregulation of Fas/CD95 ligand

2000 ◽  
Vol 111 (2) ◽  
pp. 432-440 ◽  
Author(s):  
Davide Gibellini ◽  
Alessandra Bassini ◽  
Maria Carla Re ◽  
Cristina Ponti ◽  
Sebastiano Miscia ◽  
...  
Keyword(s):  
Selective Inhibition ◽  
Cd95 Ligand ◽  
Erythroid Development

Increased response preparation overshadows neurophysiological evidence of proactive selective inhibition.

2018 ◽  
Vol 11 (1) ◽  
pp. 1-17 ◽  
Author(s):  
Neil M. Drummond ◽  
Erin K. Cressman ◽  
Anthony N. Carlsen
Keyword(s):  
Selective Inhibition ◽  
Response Preparation

Selective inhibition of chemokine CCL2/MCP-1 reduces experimental pulmonary hypertension

Pneumologie ◽  
2013 ◽  
Vol 67 (05) ◽  
Author(s):  
D Kosanovic ◽  
BK Dahal ◽  
C Vroom ◽  
E Bieniek ◽  
H Ardeschir Ghofrani ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Selective Inhibition

Selective Inhibition of Thromboxane Synthetase with Dazoxiben - Basis of Its Inhibitory Effect on Platelet Adhesion

1983 ◽  
Vol 49 (02) ◽  
pp. 096-101 ◽  
Author(s):  
V C Menys ◽  
J A Davies
Keyword(s):  
Arachidonic Acid ◽  
Platelet Adhesion ◽  
Fold Increase ◽  
Selective Inhibition ◽  
Inhibitory Effect ◽  
Selective Inhibitor ◽  
Coated Glass ◽  
Thromboxane Synthetase ◽  
Pre Treatment

SummaryPlatelet adhesion to rabbit aortic subendothelium or collagen-coated glass was quantitated in a rotating probe device by uptake of radio-labelled platelets. Under conditions in which aspirin had no effect, dazoxiben, a selective inhibitor of thromboxane synthetase, reduced platelet adhesion to aortic subendothelium by about 40% but did not affect adhesion to collagen-coated glass. Pre-treatment of aortic segments with 15-HPETE, a selective inhibitor of PGI2-synthetase, abolished the inhibitory effect of dazoxiben on adhesion. Concentrations of 6-oxo-PGFlα in the perfusate were raised in the presence of dazoxiben alone, and following addition of thrombin (10 units/ml) there was a 2-3 fold increase in concentration. Perfusion of damaged aorta with platelets labelled with (14C)-arachidonic acid in the presence of thrombin and dazoxiben resulted in the appearance of (14C)-labelled-6-oxo-PGFiα. Inhibition of thromboxane synthetase limits platelet adhesion probably by promoting vascular synthesis of PGI2 from endoperoxides liberated from adherent platelets, which subsequently promotes detachment of cells from the surface.

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