PHORBOL ESTER TREATMENT OF U937 CELLS WITH ALTERED PROTEIN-KINASE-C CONTENT AND DISTRIBUTION INDUCES CELL-DEATH RATHER THAN DIFFERENTIATION

Overexpression of protein kinase C (PKC)-zeta, an atypical PKC isoform , in U937 cells stimulates certain parameters of phenotypic maturation and increases expression of endogenous alpha and beta PKC isoforms. I n response to 12-0-tetradecanoylphorbol-13-acetate (TPA), parental U93 7 cells displayed growth arrest and differentiated into a monocyte/mac rophage-like cell line, while PKC-zeta cells underwent death. The abil ity of GF109203X to inhibit TPA-induced death of PKC-zeta cells sugges ted that activation of a conventional isoform was necessary to induce apoptosis. While exhibiting unique morphological changes, parameters i ndicative of a further degree of differentiation were not observed in TPA-treated PKC-zeta cells. TPA-induced down-regulation of PKC activit y was similar in both cells. While modest quantitative differences in individual isoform down-regulation existed, intracellular localization of isoforms prior to activation differed significantly between U937 a nd PKC-zeta cells. Expression of gadd45 was induced by TPA in PKC-zeta but not parental cells and occurred as a primary response to TPA and prior to the onset of cell death. These data suggest that the decision of a cell to undergo death or differentiation in response to phorbol esters may, in part, be modulated by alterations within the PKC signal transduction pathway.