IKKα Regulates the Mitotic Phase of the Cell Cycle by Modulating Aurora A Phosphorylation

Abstract

The IKK complex includes two catalytic components, IKKα and IKKβ, in addition to the scaffold protein IKKγ/NEMO. Even though IKKα and IKKβ share significant sequence homology, they have distinct biological roles with IKKβ regulates the classical pathway of NF-κB activation and IKKα regulates the alternative pathways. In addition, it has been shown that the IKKs regulate the proliferation of both normal and tumor cells; however, the mechanisms by which the IKKs regulate the cell cycle remain to be further defined. Here, we demonstrate that IKKα, but not IKKβ, has role in regulating the M phase of the cell cycle. IKKα siRNA knock-down resulted in increased numbers of cells in the G2/M phase of the cell cycle as compared to control and IKKβ siRNA transfected HeLa cells. This effect was associated with upregulation of cyclin B1 and Plk1 protein levels and increased histone H3 phosphorylation, consistent with a potential role of IKKα in the regulation of M phase regulatory factors. IKKα was found to be associated with Aurora A in the centrosome and regulate Aurora A phosphorylation at threonine residue 288, a site which is important in modulating its kinase activity. Taken together, these data provide the evidence that IKKα regulates the M phase of the cell cycle by modulating Aurora A phosphorylation and activation leading to the regulation of the M phase of the cell cycle.