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. 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.
de Vente
J
J
Department of Medicine, East Carolina University School of Medicine Greenville, North Carolina 27858-4354, USA.
Kiley
S
S
Garris
T
T
Bryant
W
W
Hooker
J
J
Posekany
K
K
Parker
P
P
Cook
P
P
Fletcher
D
D
Ways
D K
DK
D015703:Antigens, CD / Q000096:biosynthesis; D017209:Apoptosis / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D002461:Cell Line, Transformed; D003599:Cytoskeleton / Q000187:drug effects; D018014:Gene Transfer Techniques; D006801:Humans; D007938:Leukemia / Q000378:metabolism / Q000473:pathology; D010703:Phorbol Esters / Q000494:pharmacology*; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*
D015703:Antigens, CD; D010703:Phorbol Esters; D011493:Protein Kinase C