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Caspase-mediated proteolysis and activation of protein kinase C delta plays a central role in neutrophil apoptosis

Khwaja, A; Tatton, L; (1999) Caspase-mediated proteolysis and activation of protein kinase C delta plays a central role in neutrophil apoptosis. BLOOD , 94 (1) 291 - 301.

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Abstract

Neutrophils undergo constitutive apoptosis when aged ex vivo, Recent studies have indicated roles for Fas/CD95 and the nicotinamide adenine dinucleotide phosphate (NADPH)oxidase system in this process. We have investigated the role of protein kinase C (PKC) in neutrophil death. We show that there is proteolysis and activation of the novel isoform PKC delta in aged neutrophils and that this process is accelerated by the addition of an agonistic Fas antibody. PKC delta proteolysis occurs before the onset of any detectable features of apoptosis and pharmacologic inhibition of this enzyme inhibits neutrophil apoptosis. PKC delta cleavage and activation is dependent on caspase-8/FADD-like interleukin-1 beta converting enzyme (FLICE)-mediated processing of caspase-3/CPP32. Neutrophil survival is prolonged by the addition of broad spectrum (BD.fmk) or caspase-8 targeted (zIETD.fmk) peptide caspase inhibitors. Inhibition of PKC delta does not prevent apoptosis triggered by factor withdrawal in immature hematopoietic cells, including normal human CD34(+) progenitors indicating that within a given lineage, the mechanisms of apoptosis may be differentiation-stage-specific. Ex vivo aging of neutrophils leads to the increasing production of reactive oxygen species and this is attenuated in cells treated with either caspase or PKC delta inhibitors. Proteolytically activated PKC delta acts as a molecular link between the Fas/CD95 receptor and the NADPH-oxidase system and plays a central role in regulating the process of neutrophil apoptosis. (C) 1999 by The American Society of Hematology.

Type: Article
Title: Caspase-mediated proteolysis and activation of protein kinase C delta plays a central role in neutrophil apoptosis
Keywords: COLONY-STIMULATING FACTOR, NADPH OXIDASE ACTIVATION, NECROSIS-FACTOR-ALPHA, CELL-FREE SYSTEM, RESPIRATORY BURST, PLASMA-MEMBRANE, SIGNALING COMPLEX, DELAYS APOPTOSIS, PHOSPHOLIPASE-D, CD95 FAS/APO-1
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
URI: http://discovery.ucl.ac.uk/id/eprint/88695
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