PLATELET-ACTIVATING-FACTOR AND POLYUNSATURATED FATTY-ACIDS IN CEREBRAL-ISCHEMIA OR CONVULSIONS - INTRACELLULAR PAF-BINDING SITES AND ACTIVATION OF A FOS/JUN/AP-1 TRANSCRIPTIONAL SIGNALING SYSTEM

被引:91
作者
BAZAN, NG
SQUINTO, SP
BRAQUET, P
PANETTA, T
MARCHESELLI, VL
机构
[1] LOUISIANA STATE UNIV, MED CTR, SCH MED, DEPT BIOCHEM & MOLEC BIOL, NEW ORLEANS, LA 70112 USA
[2] LOUISIANA STATE UNIV, MED CTR, SCH MED, DEPT OPHTHALMOL, NEW ORLEANS, LA 70112 USA
[3] LOUISIANA STATE UNIV, MED CTR, SCH MED, DEPT SURG, NEW ORLEANS, LA 70112 USA
[4] LOUISIANA STATE UNIV, MED CTR, SCH MED, CTR NEUROSCI, NEW ORLEANS, LA 70112 USA
关键词
D O I
10.1007/BF02536539
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Platelet-activating factor (PAF) is a lipid mediator formed in the early response of the central nervous system to ischemia or convulsions. Free polyunsaturated fatty acids and arachidonic and docosahexaenoic acids are accumulated along with PAF. Antagonists of PAF have been found to improve cerebral blood flow and partially block the rise in free fatty acids, an effect that may arise by way of inhibition of PAF receptors or stimulation of the reacylation of free fatty acids released upon insult. Three intracellular PAF-binding sites have been identified in rat cerebral cortex. These very high-affinity binding sites are inhibited by PAF antagonists, with certain antagonists exhibiting specificity for a particular binding site. This specificity indicates heterogeneity in these binding sites. Ischemia or stimulation also leads to protooncogene transcriptional activation. Here, we discuss studies with cells in culture showing that PAF promotes transcriptional activation of immediate-early genes. PAF activates the transcription of the immediate-early genes fos and jun, whose gene products are regulators of the transcription of other genes. Transcription of fos is also activated by convulsion or ischemia in the central nervous system. The activation of these genes by PAF can be inhibited by PAF antagonists, and is apparently accomplished by way of an AP-1 transcription regulatory sequence in the promoter region of the target genes. Studies with deletion mutants show that PAF can also exert its activating properties by way of cyclic adenosine-3',5'-monophosphate-(cAMP) and Ca2+-responsive elements, and suggest that PAF is involved in an interconnected network of cell signaling that may coordinate short-term and long-term responses of cells to stimulus and injury.
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页码:1236 / 1242
页数:7
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