IKKα Regulates Estrogen-induced Cell Cycle Progression by Modulating E2F1 Expression

Abstract The IκB kinase (IKK) complex consists of the catalytic subunits IKKα and IKKβ and a regulatory subunit, IKKγ/NEMO. Even though IKKα and IKKβ share significant sequence similarity, they have distinct biological roles. It has been demonstrated that IKKs are involved in regulating the proliferation of both normal and tumor cells, although the mechanisms by which they function in this process remain to be better defined. In this study, we demonstrate that IKKα, but not IKKβ, is important for estrogen-induced cell cycle progression by regulating the transcription of the E2F1 gene as well as other E2F1-responsive genes, including thymidine kinase 1, proliferating cell nuclear antigen, cyclin E, and cdc25A. The role of IKKα in regulating E2F1 was not the result of reduced levels of cyclin D1, as overexpression of this gene could not overcome the effects of IKKα knock-down. Furthermore, estrogen treatment increased the association of endogenous IKKα and E2F1, and this interaction occurred on promoters bound by E2F1. IKKα also potentiated the ability of p300/CBP-associated factor to acetylate E2F1. Taken together, these data suggest a novel mechanism by which IKKα can influence estrogen-mediated cell cycle progression through its regulation of E2F1.