Summary Phorbol-12-myristate-13-acetate (PMA) induces p21 WAF-1 expression in human myeloid leukaemic HL-60 cells. We show that this induction is specifically mediated by protein kinase C (PKC). In addition, the PKC inhibitor Ro 31-8220 with predominant PKC-a isoform specificity almost completely inhibited PMA-induced up-regulation of p21 WAFi in HL-60 cells as well as in the myelomonocytic leukaemic U937 cells. Pretreatment of HL-60 cells with Ro 31-8220 also inhibited PMA-induced activation of c-raf-1, a known PKC a target. In the phorbol ester-tolerant HL-60 subline (PET) with PKC-P isoform deficiency PMA or bryostatin-1 induced p21 WAFI expression, but to a lesser extent than in wild-type HL-60 cells. In PET cells, Ro 31-8220 also inhibited PMA and bryostatin-1 -induced up-regulation of p21 WAFi expression. Our findings indicate that at least in HL-60 cells up-regulation of p21 WAF-1 is specifically activated by PKC. We suggest that PKC isoforms other than 1B, presumably the PKC-a isoform, are involved in this process.Cancer is characterized by profound alterations both in cell cycle control and in cellular differentiation. Such mechanisms can be studied with the help of cell line models, for example leukaemic cell lines in which both proliferation and differentiation programmes may be analysed. Phorbol ester-induced differentiation of human leukaemic myeloid HL-60 cells towards monocytelike cells is associated with growth arrest in the G, phase of the cell cycle. The CKI p21WAFJ (wild-type p53-activatedftagment-1) is a mediator of G1 cycle arrest induced by wild-type p53 protein (El-Deiry et al, 1993), and in human leukaemia p21WAFI expression may be up-regulated independently from p53 (Schwaller et al, 1995;Zhang et al, 1995;Blagosklonny et al, 1996).Phorbol esters are potent activators of protein kinase C (PKC), a family of serine-threonine protein kinases that act as a central mediators of signal transduction pathways (Castagna, 1987). In HL-60 cells concordant expression pattern of PKC-a and -0 isoenzymes is seen during phorbol ester-induced monocytic differentiation (Aihara et al, 1991;Edashige et al, 1992). To examine the role of PKC in up-regulating p21WAFJ expression, we modulated p21WAFI expression by several PKC activators and inhibitors. We also investigated the expression of c-raf-1, a protein serine-threonine kinase required for p21WAFI induction and up-stream regulation of mitogenactivated protein (MAP) kinase (Blagosklonny et al, 1995).
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