ERK/MAPK pathway is required for changes of cyclin D1 and B1 during phorbol 12-myristate 13-acetate-induced differentiation of K562 cells

Phorbol 12-myristate 13-acetate (BMA)-induced differentiation of human eryt hroleukemic K562 cells is characterized by growth arrest, morphological cha nge, and expression of megakaryocyte-specific proteins. We examined the pos sible involvement of cell cycle regulators with PMA-induced growth arrest a nd megakaryocytic differentiation of K562 cells. The concentrations of cycl in D1 and p21(Waf1/Cip1) were dramatically increased, whereas those of cycl in B1 and cdc2 were decreased, by PMA treatment. The concentrations of most cyclin-dependent kinases (Cdk2, Cdk4, and Cdk6), however, were unchanged b y PMA treatment. PD98059, a specific inhibitior of MEK1, partially prevente d the increase in cyclin D1 caused by PMA and fully reversed the down-regul ation of cyclin B1 protein seen in response to PMA treatment. Thus, it is d emonstrated here that the PMA-mediated changes of cyclin D1 and B1 are the result of a persistent increase in extracellular signal-regulated kinase/mi togen-activated protein kinase (ERK/MAPK) activity.