NF-kappa B function in growth control: Regulation of cyclin D1 expression and G(0)G(1)-to-S-Phase transition

Nuclear factor kappa B (NF-kappa B) has been implicated in the regulation o f cell proliferation, transformation, and tumor development. We proc ide ev idence for a direct link between NF-kappa B activity and cell cycle regulat ion. NF-kappa B was found to stimulate transcription of cyclin D1, a key re gulator of G(1) checkpoint control. Two NF-kappa B binding sites in the hum an cyclin D1 promoter conferred activation by NF-kappa B as well as by grow th factors. Both levels and kinetics of cyclin D1 expression during G(1) ph ase were controlled by NF-kappa B. Moreover, inhibition of NF-kappa B cause d a pronounced reduction of serum-induced cyclin D1-associated kinase activ ity and resulted in delayed phosphorylation of the retinoblastoma protein. Furthermore, NF-kappa B promotes G(1)-to-S-phase transition in mouse embryo nal fibroblasts and in T47D mammary carcinoma cells. Impaired cell cycle pr ogression of T47D cells expressing an NF-kappa B superrepressor (I kappa B alpha Delta N) could be rescued by ectopic expression of cyclin D1, Thus, N F-kappa B contributes to cell cycle progression, and one of its targets mig ht be cyclin D1.