Inhibition of "tissue" transglutaminase increases cell survival by preventing apoptosis

Treatment of the human promonocytic cell line U937 with all-trans-retinoic acid (RA) commits these cells to apoptosis, which can be triggered by simpl y increasing intracellular calcium levels by the ionophore A23187. RA treat ment of U937 cells is characterized by a decrease in Bcl-2 and marked induc tion of "tissue" transglutaminase (tTG) gene expression. In this study, we show that the inhibition of tTG expression in U937 cells undergoing apoptos is prevents their death. In fact, U937 cell-derived clones transfected with the human tTG gene in the antisense orientation showed a pronounced decrea se in apoptosis induced by several stimuli. These findings demonstrate that the Ca2+-dependent irreversible cross-linking of intracellular proteins ca talyzed by tTG represents an important biochemical event in the gene-regula ted cell death in monoblasts. In addition, our data indicate that the apopt otic program in promonocytic cells is strictly regulated by RA and that a k ey role is played by the free intracellular calcium concentration.