Journal of Biological Chemistry
Volume 284, Issue 49, 4 December 2009, Pages 33781-33788
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Mechanisms of Signal Transduction
MAPK Pathway Activation Delays G2/M Progression by Destabilizing Cdc25B*

https://doi.org/10.1074/jbc.M109.027516Get rights and content
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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.

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*

This work was supported by grants from the Australian Research Council.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S5.

1

Both authors contributed equally to this work.

3

Present address: Dept. of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, TX 77030.

2

National Health and Medical Research Council Senior Research Fellow.