Evidence that activation of MEK1,2/erk1,2 signal transduction pathway is necessary for calcitriol-induced differentiation of HL-60 cells.

Calcitriol (1,25-dihydroxyvitamin D3) induces differentiation and inhibits proliferation of human promyelocytic leukemia cells. The mechanisms involved in the regulation of these processes are not clearly understood. Previous studies have shown that calcitriol mediates cell differentiation not only by interaction with nuclear vitamin D receptor, but also by numerous rapid, membrane--mediated effects. Since in the light of past studies, involvement of raf/MEK1,2/erk1,2 signal transduction pathway in calcitriol-induced cell differentiation was questionable, another attempt was undertaken in this study in order to investigate the problem. PD 98059, the specific inhibitor of MEK1 and MEK2 was found to inhibit calcitriol-induced monocytic differentiation of HL-60 cells. This finding proves that activation of the raf/MEK1,2/erk1,2 signal transduction pathway is essential for monocytic differentiation of human leukemia cells. The results reported in this paper suggest that inhibition of protein kinase C, which upstream regulates activation of erk1 and erk2, may be bypassed during the process of calcitriol-induced leukemia cell differentiation.