Expression of MAP3 kinase COT1 is up-regulated by 1,25-dihydroxyvitamin D3 in parallel with activated c-jun during differentiation of human myeloid leukemia cells

The role of MAP kinase pathways in 1,25-dihydroxyvitamin D3 (1,25D)-induced differentiation of myeloid leukemia cells is well established, but the mechanisms by which 1,25D activates these pathways are not entirely clear. Following the finding that kinase suppressors of ras (KSR) 1 and 2 are directly regulated by 1,25D and participate in the monocytic differentiation process, we investigated if the COT1 oncogene (Tpl2 in the rat), known to interact with human KSR2 (hKSR2), is also involved in 1,25D-induced differentiation in leukemia cells. Here we report that the exposure of HL60 and U937 myeloid leukemia cells to 1,25D increases COT1 expression in a concentration-dependent manner. However, COT1 appears to have a differentiation-limiting role in these cells, as an exposure of HL60 and U937 cells to a pharmacological inhibitor of COT1 kinase activity, 4-(3-chloro-4-fluorophenylamino)-6-(pyridin-3-yl-methylamino-3-cyano-[1–7]-naphthyridine, results in increased 1,25D-induced differentiation. These findings provide an additional insight into the 1,25D-regulation of MAPK pathways that contribute to monocytic differentiation process of myeloid leukemia cells.