Farnesol (FOH) inhibits the CDP-choline pathway for PtdCho (phosphatidylcholine) synthesis, an activity that is involved in subsequent induction of apoptosis. Interestingly, the rate-limiting enzyme in this pathway, CCTα (CTP:phosphocholine cytidylyltransferase α), is rapidly activated, cleaved by caspases and exported from the nucleus during FOH-induced apoptosis. The purpose of the present study was to determine how CCTα activity and PtdCho synthesis contributed to induction of apoptosis by FOH and oleyl alcohol. Contrary to previous reports, we show that the initial effect of FOH and oleyl alcohol was a rapid (10–30 min) and transient activation of PtdCho synthesis. During this period, the mass of DAG (diacylglycerol) decreased by 40%, indicating that subsequent CDP-choline accumulation and inhibition of PtdCho synthesis could be due to substrate depletion. At later time points (>1 h), FOH and oleyl alcohol promoted caspase cleavage and nuclear export of CCTα, which was prevented by treatment with oleate or DiC8 (dioctanoylglycerol). Protection from FOH-induced apoptosis required CCTα activity and PtdCho synthesis since (i) DiC8 and oleate restored PtdCho synthesis, but not endogenous DAG levels, and (ii) partial resistance was conferred by stable overexpression of CCTα and increased PtdCho synthesis in CCTα-deficient MT58 cells. These results show that DAG depletion by FOH or oleyl alcohol could be involved in inhibition of PtdCho synthesis. However, decreased DAG was not sufficient to induce apoptosis provided nuclear CCTα and PtdCho syntheses were sustained.
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Research Article|
December 06 2005
Induction of apoptosis by lipophilic activators of CTP:phosphocholine cytidylyltransferase α (CCTα)
Thomas A. Lagace;
Thomas A. Lagace
1
1Atlantic Research Centre, Departments of Pediatrics and Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS, Canada B3H 4H7
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Neale D. Ridgway
Neale D. Ridgway
2
1Atlantic Research Centre, Departments of Pediatrics and Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS, Canada B3H 4H7
2To whom correspondence should be addressed, at Rm C306, CRC Bldg, Dalhousie University, 5849 University Avenue, Halifax, NS, Canada B3H 4H7 (email nridgway@dal.ca).
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Publisher: Portland Press Ltd
Received:
June 25 2005
Revision Received:
August 02 2005
Accepted:
August 15 2005
Accepted Manuscript online:
August 15 2005
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2005
Biochem J (2005) 392 (3): 449–456.
Article history
Received:
June 25 2005
Revision Received:
August 02 2005
Accepted:
August 15 2005
Accepted Manuscript online:
August 15 2005
Citation
Thomas A. Lagace, Neale D. Ridgway; Induction of apoptosis by lipophilic activators of CTP:phosphocholine cytidylyltransferase α (CCTα). Biochem J 15 December 2005; 392 (3): 449–456. doi: https://doi.org/10.1042/BJ20051021
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