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Molecular and Cellular Biology, July 2002, p. 4851-4862, Vol. 22, No. 13
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.13.4851-4862.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Caspase Processing and Nuclear Export of CTP:Phosphocholine Cytidylyltransferase {alpha} during Farnesol-Induced Apoptosis

Thomas A. Lagace, Jessica R. Miller, and Neale D. Ridgway*

Atlantic Research Centre, Departments of Pediatrics and Biochemistry & Molecular Biology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4H7

Received 6 November 2001/ Returned for modification 8 January 2002/ Accepted 29 March 2002

CTP:phosphocholine cytidylyltransferase alpha (CCT{alpha}) is a nuclear enzyme that catalyzes the rate-limiting step in the CDP-choline pathway, the primary route for synthesis of phosphatidylcholine (PtdCho) in eukaryotic cells. Induction of apoptosis by farnesol (FOH) and other cytotoxic drugs has been shown to alter PtdCho synthesis via the CDP-choline pathway. Here we report that FOH-induced apoptosis in CHO cells caused a dose-dependent activation of CCT{alpha} and inhibition of the final step in the pathway, resulting in a biphasic effect on PtdCho synthesis. Activation of CCT{alpha} was accompanied by enzyme translocation to the nuclear envelope within 30 min of FOH addition to cells. Following translocation to membranes, CCT{alpha} was exported from the nucleus and underwent caspase-mediated proteolysis that coincided with poly(ADP-ribose) polymerase cleavage. Site-directed mutagenesis and in vivo and in vitro expression studies mapped a caspase 6 and/or 8 cleavage site to TEED28{downarrow}G, the final residue in the CCT{alpha} nuclear localization signal. Nuclear export of CCT{alpha} appeared to be an active process in FOH-treated CHO cells that was independent of caspase removal of the nuclear localization signal. Caspase cleavage of CCT{alpha} occurred during UV or chelerythrine-induced apoptosis; however, nuclear membrane translocation and nuclear export were not evident under these conditions. Thus, caspase cleavage of CCT{alpha} was a late feature of several apoptotic programs that occurred in the nucleus or at the nuclear envelope. Activation and nuclear export of CCT{alpha} were early events in FOH-induced apoptosis that contributed to altered PtdCho synthesis and, in conjunction with caspase cleavage, excluded CCT{alpha} from the nucleus.

* Corresponding author. Mailing address: Atlantic Research Centre, Rm. C306, Clinical Research Centre, 5849 University Ave., Dalhousie University, Halifax, Nova Scotia, Canada B3H 4H7. Phone: (902) 494-7133. Fax: (902) 494-1394. E-mail: nridgway{at}is.dal.ca.

Molecular and Cellular Biology, July 2002, p. 4851-4862, Vol. 22, No. 13
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.13.4851-4862.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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