ERK/MAPK Pathway Is Required for Changes of Cyclin D1 and B1 During Phorbol 12-Myristate 13-Acetate-Induced Differentiation of K562 Cells

Abstract

Phorbol 12‐myristate 13‐acetate (PMA)‐induced differentiation of human erythroleukemic K562 cells is characterized by growth arrest, morphological change, and expression of megakaryocyte‐specific proteins. We examined the possible involvement of cell cycle regulators with PMA‐induced growth arrest and megakaryocytic differentiation of K562 cells. The concentrations of cyclin D1 and p21Waf1/Cip1 were dramatically increased, whereas those of cyclin B1 and cdc2 were decreased, by PMA treatment. The concentrations of most cyclin‐dependent kinases (Cdk2, Cdk4, and Cdk6), however, were unchanged by PMA treatment. PD98059, a specific inhibitior of MEK1, partially prevented the increase in cyclin D1 caused by PMA and fully reversed the down‐regulation of cyclin B1 protein seen in response to PMA treatment. Thus, it is demonstrated here that the PMA‐mediated changes of cyclin D1 and B1 are the result of a persistent increase in extracellular signal‐regulated kinase/mitogen‐activated protein kinase (ERK/MAPK) activity.