International Immunology, Vol 10, 877-889, Copyright © 1998 by Oxford University Press
L Drew, R Kumar, D Bandyopadhyay and S Gupta
The role of the basal activity of the serine/threonine protein kinase,
protein kinase C (PKC) in the regulation of anti-CD95-induced apoptosis in
Jurkat T cells was investigated. The PKC-specific inhibitor GF 109203X and
the proposed cPKC-specific inhibitor Go 6976, in a concentration-dependent
manner, increased the percentage of cells undergoing apoptosis induced by
anti-CD95 mAb as demonstrated by propidium iodide (PI) staining, TUNEL
assay and DNA fragmentation by gel electrophoresis. Furthermore, Go 6976
and GF 109203X abrogated phorbol myristate acetate-induced inhibition of
anti-CD95-induced apoptosis. To examine the molecular mechanism by which
PKC modulates anti-CD95-induced apoptosis, the effects of Go 6976 on known
effector and regulatory molecules of cell death were studied. Increased
recruitment of cells undergoing apoptosis was associated with enhanced
anti-CD95-induced proteolytic cleavage of the most receptor-proximal
cysteine protease caspase-8, subsequent cleavage and activation of the
machinery protease caspase-3, and cleavage of the caspase substrates
DNA-dependent protein kinase catalytic subunit, poly-(ADP-ribose)
polymerase and lamin B1. CD95 and FADD protein levels in Jurkat T cells
were not altered by Go 6976 treatment. In addition, Go 6976 did not alter
protein levels and subcellular distribution of the anti-apoptotic molecules
Bcl-2 and Bcl-xL. These data suggest indirectly that basal PKC activity
acts at an early stage in the anti-CD95-induced caspase pathway to
attenuate subsequent activation of downstream effector molecules and
associated apoptosis in Jurkat T cells.
ARTICLES
Inhibition of the protein kinase C pathway promotes anti-CD95-induced apoptosis in Jurkat T cells
Department of Medicine, University of California, Irvine 92697, USA.
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