NF-κB Function in Growth Control: Regulation of Cyclin D1 Expression and G₀/G₁-to-S-Phase Transition

Abstract

Nuclear factor kappa B (NF-κB) has been implicated in the regulation of cell proliferation, transformation, and tumor development. We provide evidence for a direct link between NF-κB activity and cell cycle regulation. NF-κB was found to stimulate transcription of cyclin D1, a key regulator of G₁checkpoint control. Two NF-κB binding sites in the human cyclin D1 promoter conferred activation by NF-κB as well as by growth factors. Both levels and kinetics of cyclin D1 expression during G₁phase were controlled by NF-κB. Moreover, inhibition of NF-κB caused a pronounced reduction of serum-induced cyclin D1-associated kinase activity and resulted in delayed phosphorylation of the retinoblastoma protein. Furthermore, NF-κB promotes G₁-to-S-phase transition in mouse embryonal fibroblasts and in T47D mammary carcinoma cells. Impaired cell cycle progression of T47D cells expressing an NF-κB superrepressor (IκBαΔN) could be rescued by ectopic expression of cyclin D1. Thus, NF-κB contributes to cell cycle progression, and one of its targets might be cyclin D1.

ACKNOWLEDGMENTS

We thank Alexandra Bohne, Uta Fischer, Heidi Riedel, and Heidrun Peter for excellent technical assistance.

This work was supported in part by grants from the Deutsche Forschungsgemeinschaft (SFB344) to C.S. and M.S. and by a grant from the Fond der Chemischen Industrie to M.S.