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 G(2) phase delays entry into mitosis; however, the role of the MAPK pathway during G(2)/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 G(2) phase delay independent of known G(2) phase checkpoint pathways but was specifically dependent on MAPK/extracellular signal-regulated kinase kinase (MEK1). Activation of MAPK signaling also blocked exit from a G(2) phase checkpoint arrest. Both the G(2) phase delay and blocked exit from the G(2) checkpoint arrest were mediated by the MEK1-dependent destabilization of the critical G(2)/M regulator cdc25B. Reintroduction of cdc25B overcame the MEK1-dependent G(2) phase delay. Thus, we have demonstrated a new function for MEK1 that controls G(2)/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 G(2) phase checkpoint arrest.