Regulation of c-Myc and Max in megakaryocytic and monocytic-macrophagic differentiation of K562 cells induced by protein kinase C modifiers: c-Myc isdown-regulated but does not inhibit differentiation

We have studied the regulation and role of c-Myc and Max in the differentia tion pathways induced in K562 cells by 12-O-tetradecanoyl phorbol-13 acetat e (TPA) and staurosporine, an activator and inhibitor, respectively, of pro tein kinase C (PKC), We found that staurosporine induced megakaryocytic dif ferentiation, as revealed by the cellular ultrastructure, platelet formatio n, and DNA endoreduplicatian. In contrast, TPA induced a differentiated phe notype that more closely resembled that of the monocyte-macrophage lineage. c-myc expression was down-regulated in K562 differentiated by both TPA and staurosporine, whereas max expression did not change in either case. Altho ugh PKC enzymatic activity was low in cells terminally differentiated with TPA and staurosporine, inhibition of PKC activity by itself did not induce c-myc down-regulation. We conclude that the c-myc gene is switched off as a consequence of the differentiation process triggered by these drugs in a m anner independent from PKC, Ectopic overexpression of c-Myc in K562 cells d id not affect the monocytic-macrophagic and megakaryocytic differentiation, indicating that c-Myc suppression is not required for these processes in K 562, Similarly, both differentiation pathways were not affected by Max over expression or by concomitant overexpression of c-Myc and Max. This result i s in contrast with the inhibition of erythroid differentiation of K562 exer ted by c-Myc, suggesting divergent roles for c-Myc/Max, depending on the di fferentiation pathway.