IKKalpha regulates the mitotic phase of the cell cycle by modulating Aurora A phosphorylation.

The IKK complex includes two catalytic components, IKKalpha and IKKbeta, in addition to the scaffold protein IKKgamma/NEMO. Even though IKKalpha and IKKbeta share significant sequence homology, they have distinct biological roles with IKKbeta regulates the classical pathway of NF-kappaB activation and IKKalpha 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 IKKalpha, but not IKKbeta, has role in regulating the M phase of the cell cycle. IKKalpha siRNA knock -down resulted in increased numbers of cells in the G(2)/M phase of the cell cycle as compared to control and IKKbeta 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 IKKalpha in the regulation of M phase regulatory factors. IKKalpha 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 IKKalpha 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.