Nucleotide requirements for the in vitro activation of the apoptosis protein-activating factor-1-mediated caspase pathway

被引:135
|
作者
Genini, D
Budihardjo, I
Plunkett, W
Wang, XD
Carrera, CJ
Cottam, HB
Carson, DA
Leoni, LM [1 ]
机构
[1] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA
[2] Univ Calif San Diego, Sam & Rose Stein Inst Res Aging, La Jolla, CA 92093 USA
[3] Univ Texas, SW Med Ctr, Dept Biochem, Howard Hughes Med Inst, Dallas, TX 75235 USA
[4] Univ Texas, MD Anderson Canc Ctr, Dept Clin Invest, Houston, TX 77030 USA
关键词
D O I
10.1074/jbc.275.1.29
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
Adenine deoxynucleosides, such as 2-chloradeoxyadenosine (2CdA) and fludarabine, induce apoptosis in quiescent lymphocytes, and are thus useful drugs for the treatment of indolent lymphoproliferative diseases, We previously demonstrated that that the 5'-triphosphate metabolite of 2CdA (2CdATP), similar to dATP, can co-operate with cytochrome c and apoptosis protein-activating factor-1 (APAF-1) to trigger a caspase pathway in a HeLa cell-free system. We used a fluorometry-based assay of caspase activation to extend the analysis to several other clinically relevant adenine deoxynucleotides in B-chronic lymphocytic leukemia extracts. The nucleotide-induced caspase activation displayed typical Michaelis-Menten kinetics. As estimated by the V-max/K-m ratios, the relative efficiencies of different nucleotides were Ara-ATP > 9-fluoro-9-beta-D-arabinofuranosyladenine 5'-triphosphate > dATP > SCdATP > 9-beta-D-arabinofuranosylguanine 5'-triphosphate > dADP > ATP. In contrast to dADP, both ADP and its nonhydrolyzable alpha,beta-methylphosphonate analog were strong inhibitors of APAF-1-dependent caspase activation. The hierarchy of nucleotide activation was confirmed in a fully reconstituted system using recombinant APAF-1 and recombinant procaspase-9. These results suggest that the potency of adenine deoxynucleotides as co-factors for APAF-1-dependent caspase activation is due bath to stimulation by the 5'-triphosphates and lack of inhibition by the 5'-diphosphates, The capacity of adenine deoxynucleoside metabolites to activate the apoptosome pathway may be an additional biochemical mechanism that plays a role in the chemotherapy of indolent lymphoproliferative diseases.
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页码:29 / 34
页数:6
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