Barré Benjamin, Perkins Neil D
Division of Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee, Scotland, UK.
EMBO J. 2007 Nov 28;26(23):4841-55. doi: 10.1038/sj.emboj.7601899. Epub 2007 Oct 25.
Aberrantly active NF-kappaB complexes can contribute to tumorigenesis by regulating genes that promote the growth and survival of cancer cells. We have investigated NF-kappaB 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 IkappaB kinase (IKK)alpha, IKKbeta, Akt and Chk1. The coordinated binding of NF-kappaB 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-kappaB subunits in G1 and G2 phases, where Chk1 is inactive. However, in S-phase, Akt is inactivated, while Chk1 phosphorylates RelA and associates with IKKalpha, inhibiting the processing of the p100 (NF-kappaB2) subunit, which also plays a critical role in the regulation of these genes. These data reveal a complex regulatory network integrating NF-kappaB with the DNA-replication checkpoint and the expression of critical regulators of cell proliferation.
异常激活的核因子-κB复合物可通过调控促进癌细胞生长和存活的基因来促进肿瘤发生。我们研究了细胞周期中的核因子-κB，发现其调控关键原癌基因G1期表达的能力受到IκB激酶（IKK）α、IKKβ、Akt和Chk1整合活性的调节。核因子-κB亚基与细胞周期蛋白D1、c-Myc和Skp2启动子的协同结合是动态的，在G1、S和G2期启动子占据和RelA（p65）磷酸化发生明显变化，同时伴随着从共激活因子募集到共抑制因子募集的转变。在G1和G2期，Chk1无活性，Akt活性是IKK依赖的核因子-κB亚基磷酸化所必需的。然而，在S期，Akt失活，而Chk1使RelA磷酸化并与IKKα结合，抑制p100（核因子-κB2）亚基的加工，p100亚基在这些基因的调控中也起关键作用。这些数据揭示了一个复杂的调控网络，将核因子-κB与DNA复制检查点及细胞增殖关键调节因子的表达整合在一起。
