EXPRESSION OF CD38 INCREASES INTRACELLULAR CALCIUM-CONCENTRATION AND REDUCES DOUBLING TIME IN HELA AND 3T3 CELLS

CD38 is a bifunctional ectoenzyme, predominantly expressed on hematopo ietic cells during differentiation, that catalyzes the synthesis (cycl ase) and the degradation (hydrolase) of cyclic ADP-ribose (cADPR), a p owerful calcium mobilizer from intracellular stores, Due to the well e stablished role of calcium levels in the regulation of apoptosis, prol iferation, and differentiation, the CD38/cADPR system seems to be a li kely candidate involved in the control of these fundamental processes. The ectocellular localization of the cyclase activity, however, contr asts with the intracellular site of action of cADPR. Here we demonstra te that ectocellular expression of human CD38 in CD38(-) HeLa and 3T3 cells results in intracellular CD38 substrate (NAI(+) + NADH) consumpt ion and product (cADPR) accumulation. Furthermore, a causal relationsh ip is established between presence of intracellular cADPR, partial dep letion of thapsigargin-sensitive calcium stores, increase in basal fre e cytoplasmic calcium concentration, and decrease of cell doubling tim e. The significant shortening of the S phase in CD38(+) HeLa cells, as compared with controls, demonstrates an effect of intracellular cADPR on the mammalian cell cycle.