MAPK pathway activation delays G2/M progression by destabilizing Cdc25B.
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.
Diamantina Institute for Cancer Immunology and Metabolic Medicine, University of Queensland, Brisbane 4102, Queensland, Australia.
Puji
P
Astuti
Tanya
T
Pike
Charlotte
C
Widberg
Elizabeth
E
Payne
Angus
A
Harding
John
J
Hancock
Brian
B
Gabrielli
D000818:Animals; D002453:Cell Cycle; D002455:Cell Division; D016195:G2 Phase; D015971:Gene Expression Regulation, Enzymologic; D006367:HeLa Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D008938:Mitosis; D016296:Mutagenesis; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate; D014981:Xenopus; D020687:cdc25 Phosphatases / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D034741:RNA, Small Interfering; D048051:p38 Mitogen-Activated Protein Kinases; C517008:CDC25B protein, human; D020687:cdc25 Phosphatases; D013755:Tetradecanoylphorbol Acetate