MAPK pathway activation delays G2/M progression by destabilizing Cdc25B

Abstract

Activation of the mitogen-activated protein kinase (MAPK) pathway by growth factors or phorbol esters during G2 phase delays entry into mitosis; however, the role of the MAPK pathway during G2/ M progression remains controversial. Here, we demonstrate that activation of the MAPK pathway with either epidermal growth factor or 12-O-tetradecanoylphorbol-13-acetate induces a G2 phase delay independent of known G2 phase checkpoint pathways but was specifically dependent on MAPK/extracellular signal-regulated kinase kinase (MEK1). Activation of MAPK signaling also blocked exit from a G2 phase checkpoint arrest. Both the G2 phase delay and blocked exit from the G2 checkpoint arrest were mediated by the MEK1-dependent destabilization of the critical G2/M regulator cdc25B. Reintroduction of cdc25B overcame the MEK1-dependent G2 phase delay. Thus, we have demonstrated a new function for MEK1 that controls G2/M progression by regulating the stability of cdc25B. This represents a novel mechanism by which factors that activate MAPK signaling can influence the timing of entry into mitosis, particularly exit from a G2 phase checkpoint arrest. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.