A cell cycle regulatory network controlling NF-κB subunit activity and function (Retracted article. See vol. 33, pg. 1978, 2014)
A cell cycle regulatory network controlling NF-κB subunit activity and function (Retracted article. See vol. 33, pg. 1978, 2014)
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DOI：
10.1038/sj.emboj.7601899
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发表时间：
2007-11-01
期刊：
影响因子：
11.4
通讯作者：
Perkins, Neil D.
中科院分区：
文献类型：
--
作者：
Barre, Benjamin;Perkins, Neil D.
异常活性的NF-κ B复合物可通过调节促进癌细胞生长和存活的基因而促成肿瘤发生。我们研究了NF-κ B在细胞周期中的作用，发现其调节关键原癌基因G1期表达的能力受到I κ B激酶（IKK）α、IKK β、Akt和Chk 1的整合活性的调节。NF-κ B亚基与细胞周期蛋白D1、c-Myc和Skp 2启动子的协同结合是动态的，在G1、S和G2期发生启动子占据和RelA（p65）磷酸化的明显变化，伴随着从辅激活因子到辅阻遏因子募集的转换。Akt活性是NF-κ B B亚基在G1和G2期IKK依赖性磷酸化所必需的，其中Chk 1是无活性的。然而，在S期，Akt失活，而Chk 1磷酸化RelA并与IKK α结合，抑制p100（NF-κ B2）亚基的加工，这也在这些基因的调控中起着关键作用。这些数据揭示了一个复杂的调节网络，它将NF-κ B与DNA复制检查点和细胞增殖关键调节因子的表达整合在一起。
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.