A cell cycle regulatory network controlling NF-B subunit activity and function

Aberrantly active NF-B complexes can contribute to tumorigenesis by regulating genes that promote the growth and survival of cancer cells. We have investigated NF-B 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 IB kinase (IKK), IKK, Akt and Chk1. The coordinated binding of NF-B 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-B subunits in G1 and G2 phases, where Chk1 is inactive. However, in S-phase, Akt is inactivated, while Chk1 phosphorylates RelA and associates with IKK, inhibiting the processing of the p100 (NF-B2) subunit, which also plays a critical role in the regulation of these genes. These data reveal a complex regulatory network integrating NF-B with the DNA-replication checkpoint and the expression of critical regulators of cell proliferation.