UP-REGULATION OF P21(WAF1) EXPRESSION IN MYELOID CELLS IS ACTIVATED BY THE PROTEIN-KINASE-C PATHWAY

Phorbol-12-myristate-13-acetate (PMA) induces p21(WAF-1) expression in human myeloid leukaemic HL-60 cells. We show that this induction is s pecifically mediated by protein kinase C (PKC). In addition, the PKC i nhibitor Po 31-8220 with predominant PKC-alpha isoform specificity alm ost completely inhibited PMA-induced up-regulation of p21(WAF1) in HL- 60 cells as well as in the myelomonocytic leukaemic U937 cells. Pretre atment of HL-60 cells with Po 31-8220 also inhibited PMA-induced activ ation of c-raf-1, a known PKC a target. In the phorbol ester-tolerant HL-60 subline (PET) with PKC-beta isoform deficiency PMA or bryostatin -l induced p21(WAF1) expression, but to a lesser extent than in wild-t ype HL-60 cells. In PET cells, Po 31-8220 also inhibited PMA and bryos tatin-l-induced up-regulation of p21(WAF1) expression. Our findings in dicate that at least in HL-60 cells up-regulation of p21(WAF-1) is spe cifically activated by PKC. We suggest that PKC isoforms other than be ta, presumably the PKC-alpha isoform, are involved in this process.