Cell Growth & Differentiation, Vol 6, Issue 4 371-382, Copyright © 1995 by American Association of Cancer Research

ARTICLES

Phorbol ester treatment of U937 cells with altered protein kinase C content and distribution induces cell death rather than differentiation

J de Vente, S Kiley, T Garris, W Bryant, J Hooker, K Posekany, P Parker, P Cook, D Fletcher and DK Ways
Department of Medicine, East Carolina University School of Medicine Greenville, North Carolina 27858-4354, USA.

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. In response to 12-O-tetradecanoylphorbol-13-acetate (TPA), parental U937 cells displayed growth arrest and differentiated into a monocyte/macrophage-like cell line, while PKC-zeta cells underwent death. The ability of GF109203X to inhibit TPA-induced death of PKC-zeta cells suggested that activation of a conventional isoform was necessary to induce apoptosis. While exhibiting unique morphological changes, parameters indicative of a further degree of differentiation were not observed in TPA-treated PKC-zeta cells. TPA-induced down-regulation of PKC activity 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 and 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.

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