Recent reports have claimed that activation of protein kinase C (PKC)-beta is sufficient for both differentiation and apoptosis in promyeloid HL60 cells. Phorbol esters which differentially activate PKC isoenzymes in vitro were used to induce differentiation and apoptosis in U937 cells; TPA and Dopp activate all U937 PKC isoenzymes, except PKC-zeta and Doppa activate only PKC-beta l. At concentrations of Doppa below 50 nM, only PKC-beta l was activated by 2 min and apoptosis was induced, but there was no differentiation of cells towards monocytes. TPA (1-25 nM) and Dopp (5-100 nM) activated PKC-alpha, -beta l and-gamma within 2 min and induced differentiation, but only increased apoptosis at the highest concentrations used. Thus, initial activation of PKC-beta l is insufficient for differentiation of U937 cells, but may lead to the induction of apoptosis.