Schumm Katie, Rocha Sonia, Caamano Jorge, Perkins Neil D
College of Life Sciences, Division of Gene Regulation and Expression, University of Dundee, Dundee, UK.
EMBO J. 2006 Oct 18;25(20):4820-32. doi: 10.1038/sj.emboj.7601343. Epub 2006 Sep 21.
The p52/p100 nuclear factor kappa B (NF-kappaB) subunit (NF-kappaB2) is aberrantly expressed in many tumour types and has been implicated as a regulator of cell proliferation. Here, we demonstrate that endogenous p52 is a direct regulator of Cyclin D1 expression. However, stimulation of Cyclin D1 expression alone cannot account for all the cell cycle effects of p52/p100 and we also find that p52 represses expression of the Cyclin-dependent kinase inhibitor p21(WAF/CIP1). Significantly, this latter effect is dependent upon basal levels of the tumour suppressor p53. By contrast, p52 cooperates with p53 to regulate other known p53 target genes such as PUMA, DR5, Gadd45alpha and Chk1. p52 associates directly with these p53-regulated promoters where it regulates coactivator and corepressor binding. Moreover, recruitment of p52 is p53 dependent and does not require p52-DNA-binding activity. These results reveal a complex role for p52 as regulator of cell proliferation and p53 transcriptional activity. Furthermore, they imply that in some cell types, p52 can regulate p53 function and influence p53-regulated decision-making following DNA damage and oncogene activation.
p52/p100核因子κB（NF-κB）亚基（NF-κB2）在多种肿瘤类型中异常表达，并被认为是细胞增殖的调节因子。在此，我们证明内源性p52是细胞周期蛋白D1表达的直接调节因子。然而，单独刺激细胞周期蛋白D1的表达并不能解释p52/p100对所有细胞周期的影响，我们还发现p52可抑制细胞周期蛋白依赖性激酶抑制剂p21（WAF/CIP1）的表达。重要的是，后一种效应取决于肿瘤抑制因子p53的基础水平。相比之下，p52与p53协同调节其他已知的p53靶基因，如PUMA、DR5、Gadd45α和Chk1。p52直接与这些p53调节的启动子结合，在那里它调节共激活因子和共抑制因子的结合。此外，p52的募集依赖于p53，且不需要p52的DNA结合活性。这些结果揭示了p52作为细胞增殖调节因子和p53转录活性调节因子的复杂作用。此外，它们表明在某些细胞类型中，p52可以调节p53功能，并影响DNA损伤和癌基因激活后p53调节的决策过程。
