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J Biol Chem, Vol. 274, Issue 39, 27726-27733, September 24, 1999
From the Mammalian group IIA phospholipase
A2 (PLA2) is believed to play important
roles in inflammation, cell injury, and tumor resistance. However, the
cellular site of action has not been clearly defined as it has long
been recognized that group IIA PLA2 is both a secretory and
mitochondrial protein. The purpose of this study was to determine the
subcellular target of the group IIA PLA2 and its role in
apoptosis stimulated by growth factor withdrawal. Cloning of the rat
liver group IIA PLA2 demonstrated a typical secretory
signal and no alternative splicing of the primary transcript. When a
sequence including the signal peptide and first 8 residues in the
mature enzyme or the entire PLA2 (including the signal
peptide) was fused to enhanced green fluorescent protein, the fusion
protein was directed to the secretory pathway rather than mitochondria
in baby hamster kidney (BHK) cells. To examine the role of group IIA
PLA2 in cell injury, wild type (wt) rat group IIA
PLA2 and a mutant group IIA PLA2 containing a
His-47
Secretory Group IIA Phospholipase A2 Generates
Anti-apoptotic Survival Signals in Kidney Fibroblasts
, Department of Cellular and Structural
Biology, The University of Texas Health Science Center at San Antonio,
San Antonio, Texas 78284-7762 and the § Department of Cell
Biology and Anatomy, University of North Carolina,
Chapel Hill, North Carolina 27599-7090
Gln mutation (at the catalytic center) were transfected into
BHK cells and cells stably expressing these constructs were isolated.
After deprivation of growth factors, both normal BHK cells and BHK
cells expressing mutant PLA2 underwent massive apoptosis,
while BHK cells expressing wt PLA2 showed considerable
resistance to growth factor withdrawal-induced apoptosis. The secretory
PLA2 inhibitors 12-epi-scalaradial and aristolochic acid abrogated resistance to apoptosis in the wt PLA2 expressing cells. These two inhibitors did not induce
cell death in the presence of fetal bovine serum, suggesting that they induce cell death by blocking PLA2 generated survival
signals. This study demonstrates that group IIA PLA2
generates anti-apoptotic survival signals in BHK cells targeting the
secretory pathway, and suggests that high levels of group IIA
PLA2 accumulated at inflammatory sites may not only
regulate inflammation, but also may protect cells from unnecessary
death induced by pro-inflammatory agents.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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