Inhibition by differentiation-inducing agents of wild-type p53-dependent apoptosis in HL-60 cells.

The product of the p53 tumor-suppressor gene has been shown to function in apoptosis and cell cycle regulation. However, there is little information regarding the regulation of apoptosis in cell differentiation. We investigated the relationship between p53-dependent apoptosis and differentiation induction using human promyelocytic leukemia HL-60 cells transfected with pMAMneo expression vectors containing dexamethasone-inducible wild-type p53 (wt-p53) cDNA inserts. Continuous exposure of the pMAMneo/wt-p53 transfectants to 1 microM dexamethasone for more than 24 h caused overexpression of wt-p53 followed by cell death with morphological changes typical of apoptosis. Using the wt-p53-inducible HL-60 cells, we examined the effects of differentiation inducers on the wt-p53-dependent apoptosis. All-trans retinoic acid (all-trans RA) at 1 nM or granulocyte macrophage colony-stimulating factor (GM-CSF) at 35 pM inhibited the wt-p53-induced apoptosis over a 42-h treatment. The apoptosis inhibition by GM-CSF, but not all-trans RA, was abolished by specific inhibitors of protein kinase C. These results suggest that extracellular signals involved in the differentiation induction could modulate the wt-p53-dependent apoptosis through protein kinase C-dependent and independent pathways.