Regulation of the G2-M cell cycle progression by the ERK5-NFκB signaling pathway

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.