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Regulation of the G2M cell cycle progression by the ERK5NF
B signaling pathway
Correspondence to Zhengui Xia: zxia{at}u.washington.edu
Elucidation of mechanisms regulating cell cycle progression is of fundamental importance for cell and cancer biology. Although several genes and signaling pathways are implicated in G1S regulation, less is known regarding the mechanisms controlling cell cycle progression through G2 and M phases. We report that extracellular signalregulated kinase 5 (ERK5), a member of the mitogen-activated protein kinases, is activated at G2M and required for timely mitotic entry. Stimulation of ERK5 activated nuclear factor
B (NF
B) through ribosomal S6 kinase 2 (RSK2)-mediated phosphorylation and degradation of I
B. Furthermore, selective inhibition of NF
B at G2M phases substantially delayed mitotic entry and inhibited transcription of G2Mspecific genes, including cyclin B1, cyclin B2, Plk-1, and cdc25B. Moreover, inhibition of NF
B at G2M diminished mitosis induced by constitutive activation of ERK5, providing a direct link between ERK5, NF
B, and regulation of G2M progression. We conclude that a novel ERK5NF
B signaling pathway plays a key role in regulation of the G2M progression.
Abbreviations used in this paper: ca, constitutive-active; dn, dominant-negative; ERK, extracellular signalregulated kinase; HFF, human foreskin fibroblast; hSMC, human artery smooth muscle cell; MBP, myelin basic protein; NF
B, nuclear factor
B; Plk, polo-like kinase; RSK, ribosomal S6 kinase; SR, super repressor; wt, wild-type.
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