• cell cycle;
  • IKK;
  • NF-κB;
  • transcription

Aberrantly active NF-κB complexes can contribute to tumorigenesis by regulating genes that promote the growth and survival of cancer cells. We have investigated NF-κB during the cell cycle and find that its ability to regulate the G1-phase expression of key proto-oncogenes is subject to regulation by the integrated activity of IκB kinase (IKK)α, IKKβ, Akt and Chk1. The coordinated binding of NF-κB subunits to the Cyclin D1, c-Myc and Skp2 promoters is dynamic with distinct changes in promoter occupancy and RelA(p65) phosphorylation occurring through G1, S and G2 phases, concomitant with a switch from coactivator to corepressor recruitment. Akt activity is required for IKK-dependent phosphorylation of NF-κB subunits in G1 and G2 phases, where Chk1 is inactive. However, in S-phase, Akt is inactivated, while Chk1 phosphorylates RelA and associates with IKKα, inhibiting the processing of the p100 (NF-κB2) subunit, which also plays a critical role in the regulation of these genes. These data reveal a complex regulatory network integrating NF-κB with the DNA-replication checkpoint and the expression of critical regulators of cell proliferation.