OVEREXPRESSION OF PROTEIN-KINASE C-ZETA STIMULATES LEUKEMIC-CELL DIFFERENTIATION

A function for protein kinase C-zeta (PKC-zeta), a member of the phorb ol ester nonresponsive atypical protein kinase C subfamily, in modulat ing differentiation was examined in the leukemic U937 cell. Transfecte d U937 cells stably overexpressing PKC-zeta displayed a longer doublin g time, lower saturation density at confluency, and an increase in adh erence to plastic as compared to control cells. PKC-zeta cells express ed a more differentiated phenotype as assessed by changes in morpholog y, surface antigen expression, and lysosomal enzyme activities and wer e distinct from parental U937 cells stimulated to differentiate by exp osure to phorbol esters. In contrast to parental U937 cells, PKC-zeta cells constitutively expressed mRNA transcripts for c-jun and a low mo bility AP-1 binding activity. Thus, PKC-zeta overexpression stimulates a type of phenotypic differentiation that differs significantly from maturation occurring upon activation of other PKC subfamilies induced by phorbol ester treatment. Increased expression of the c-jun protoonc ogene and an increase in AP-1 binding activity in PKC-zeta cells provi des a potential mechanism for explaining the altered differentiation s tatus of this cell.