IKK/NF-kappaB signaling pathway inhibits cell-cycle progression by a novel Rb-independent suppression system for E2F transcription factors.

E2Fs are key regulators of cell-cycle progression, and their transcriptional activities are regulated by histone acetyltransferases (HATs). Retinoblastoma (Rb) family proteins (pRb, p107 and p130) bind to E2Fs and inhibit their transcriptional activities by disrupting HAT binding and recruitment of histone deacetylases. In this study, we show that IkappaB kinases (IKKalpha or IKKbeta) activation inhibits cell growth and E2F-dependent transcription in normal human fibroblasts. The inhibition of E2F by IKKs was not observed in cells lacking nuclear factor (NF)-kappaB/p65; however, it was observed in cells lacking three Rb family genes. p65 disrupted the physical interaction between activator E2Fs (F2F1, E2F2 and E2F3) and the HAT cofactor transactivation/transformation-domain associated protein, resulting in a reduction in E2F-responsive gene expression. Furthermore, IKKalpha and IKKbeta directly phosphorylated E2F4, resulting in nuclear accumulation and enhanced DNA binding of the E2F4/p130 repressor complex. Our study describes a novel growth inhibitory system that functions by Rb-independent suppression of E2Fs by the IKK/NF-kappaB signaling pathway.