Journal
EMBO JOURNAL
Volume 26, Issue 23, Pages 4841-4855Publisher
WILEY
DOI: 10.1038/sj.emboj.7601899
Keywords
cell cycle; IKK; NF-kappa B; transcription
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Aberrantly active NF-kappa B complexes can contribute to tumorigenesis by regulating genes that promote the growth and survival of cancer cells. We have investigated NF-kappa 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 I kappa B kinase (IKK) alpha, IKK beta, Akt and Chk1. The coordinated binding of NF- kappa 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-kappa 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 alpha, inhibiting the processing of the p100 (NF-kappa B2) subunit, which also plays a critical role in the regulation of these genes. These data reveal a complex regulatory network integrating NF-kappa B with the DNA-replication checkpoint and the expression of critical regulators of cell proliferation.
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