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J. Cell Biol. 177 (2): 253-264

Copyright © 2007 by the Rockefeller University Press.

Article

Regulation of the G2–M cell cycle progression by the ERK5–NF{kappa}B signaling pathway

Kelly Cude1, Yupeng Wang2, Hyun-Jung Choi2, Shih-Ling Hsuan2, Honglai Zhang3, Cun-Yu Wang3, , and Zhengui Xia1,2

1 Graduate Program in Molecular and Cellular Biology and 2 Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195
3 Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI 48109

Correspondence to Zhengui Xia: zxia{at}u.washington.edu

Abstract: 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 G1–S regulation, less is known regarding the mechanisms controlling cell cycle progression through G2 and M phases. We report that extracellular signal–regulated kinase 5 (ERK5), a member of the mitogen-activated protein kinases, is activated at G2–M and required for timely mitotic entry. Stimulation of ERK5 activated nuclear factor {kappa}B (NF{kappa}B) through ribosomal S6 kinase 2 (RSK2)-mediated phosphorylation and degradation of I{kappa}B. Furthermore, selective inhibition of NF{kappa}B at G2–M phases substantially delayed mitotic entry and inhibited transcription of G2–M–specific genes, including cyclin B1, cyclin B2, Plk-1, and cdc25B. Moreover, inhibition of NF{kappa}B at G2–M diminished mitosis induced by constitutive activation of ERK5, providing a direct link between ERK5, NF{kappa}B, and regulation of G2–M progression. We conclude that a novel ERK5–NF{kappa}B signaling pathway plays a key role in regulation of the G2–M progression.

K. Cude and Y. Wang contributed equally to this paper.

Abbreviations used in this paper: ca, constitutive-active; dn, dominant-negative; ERK, extracellular signal–regulated kinase; HFF, human foreskin fibroblast; hSMC, human artery smooth muscle cell; MBP, myelin basic protein; NF{kappa}B, nuclear factor {kappa}B; Plk, polo-like kinase; RSK, ribosomal S6 kinase; SR, super repressor; wt, wild-type.

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