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Anti-apoptotic Actions of the Platelet-activating Factor Acetylhydrolase I α2 Catalytic Subunit
- Source :
- Journal of Biological Chemistry. 279:52425-52436
- Publication Year :
- 2004
- Publisher :
- Elsevier BV, 2004.
-
Abstract
- Platelet-activating factor (PAF) is an important mediator of cell loss following diverse pathophysiological challenges, but the manner in which PAF transduces death is not clear. Both PAF receptor-dependent and -independent pathways are implicated. In this study, we show that extracellular PAF can be internalized through PAF receptor-independent mechanisms and can initiate caspase-3-dependent apoptosis when cytosolic concentrations are elevated by approximately 15 pM/cell for 60 min. Reducing cytosolic PAF to less than 10 pM/cell terminates apoptotic signaling. By pharmacological inhibition of PAF acetylhydrolase I and II (PAF-AH) activity and down-regulation of PAF-AH I catalytic subunits by RNA interference, we show that the PAF receptor-independent death pathway is regulated by PAF-AH I and, to a lesser extent, by PAF-AH II. Moreover, the anti-apoptotic actions of PAF-AH I are subunit-specific. PAF-AH I alpha1 regulates intracellular PAF concentrations under normal physiological conditions, but expression is not sufficient to reduce an acute rise in intracellular PAF levels. PAF-AH I alpha2 expression is induced when cells are deprived of serum or exposed to apoptogenic PAF concentrations limiting the duration of pathological cytosolic PAF accumulation. To block PAF receptor-independent death pathway, we screened a panel of PAF antagonists (CV-3988, CV-6209, BN 52021, and FR 49175). BN 52021 and FR 49175 accelerated PAF hydrolysis and inhibited PAF-mediated caspase 3 activation. Both antagonists act indirectly to promote PAF-AH I alpha2 homodimer activity by reducing PAF-AH I alpha1 expression. These findings identify PAF-AH I alpha2 as a potent anti-apoptotic protein and describe a new means of pharmacologically targeting PAF-AH I to inhibit PAF-mediated cell death.
- Subjects :
- Programmed cell death
PAF acetylhydrolase
Molecular Sequence Data
Cell
Apoptosis
Caspase 3
Platelet Membrane Glycoproteins
Biology
PC12 Cells
Biochemistry
Receptors, G-Protein-Coupled
Lactones
Mice
Gliotoxin
Catalytic Domain
medicine
Extracellular
Animals
Platelet Activating Factor
RNA, Small Interfering
Molecular Biology
Base Sequence
Brain
Cell Biology
respiratory system
Rats
Cell biology
Mice, Inbred C57BL
Protein Subunits
Cytosol
Ginkgolides
medicine.anatomical_structure
1-Alkyl-2-acetylglycerophosphocholine Esterase
RNA Interference
lipids (amino acids, peptides, and proteins)
Diterpenes
Intracellular
Signal Transduction
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 279
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....06bb3fee467ae55af3d99113556eda95