Uncoupling farnesol-induced apoptosis from its inhibition of phosphatidylcholine synthesis

被引:49
作者
Wright, MM
Henneberry, AL
Lagace, TA
Ridgway, ND
McMaster, CR [1 ]
机构
[1] Dalhousie Univ, Atlantic Res Ctr, IWK Hlth Ctr, Dept Pediat, Halifax, NS B3H 4H7, Canada
[2] Dalhousie Univ, Atlantic Res Ctr, IWK Hlth Ctr, Dept Biochem & Mol Biol, Halifax, NS B3H 4H7, Canada
关键词
D O I
10.1074/jbc.M011552200
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
Genetic inactivation of the synthesis of phosphatidylcholine, the most abundant membrane lipid in eukaryotic cells, induces apoptosis, Administration of farnesol, a catabolite within the isoprenoid/cholesterol pathway, also induces apoptosis, The mechanism by which farnesol induces apoptosis is currently believed to be by direct competitive inhibition with diacylglycerol for cholinephosphotransferase, the final step in the phosphatidylcholine biosynthetic pathway. Our recent isolation of the first mammalian cholinephosphotransferase cDNA has enabled us to more precisely assess how farnesol affects phosphatidylcholine synthesis and the induction of apoptosis, Induced over-expression of cholinephosphotransferase in Chinese hamster ovary cells prevented the block in phosphatidylcholine biosynthesis associated with exposure to farnesol, However, induced over-expression of cholinephosphotransferase was not sufficient for the prevention of farnesol-induced apoptosis, In addition, exogenous administration of diacylglycerol prevented farnesol-induced apoptosis but did not relieve the farnesol-induced block in phosphatidylcholine synthesis. We also developed an in vitro lipid mixed micelle cholinephosphotransferase enzyme assay, as opposed to the delivery of the diacylglycerol substrate in a detergent emulsion, and demonstrated that there was no direct inhibition of cholinephosphotransferase by farnesol or its phosphorylated metabolites. The execution of apoptosis by farnesol appears to be a separate and distinct event from farnesol-induced inhibition of phosphatidylcholine biosynthesis and instead likely occurs through a diacylglycerol-mediated process that is downstream of phosphatidylcholine synthesis.
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页码:25254 / 25261
页数:8
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