Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
Mol Cell. 2012 Dec 14;48(5):799-810. doi: 10.1016/j.molcel.2012.09.020. Epub 2012 Oct 24.
The p53 tumor suppressor utilizes multiple mechanisms to selectively regulate its myriad target genes, which in turn mediate diverse cellular processes. Here, using conventional and single-molecule mRNA analyses, we demonstrate that the nucleoporin Nup98 is required for full expression of p21, a key effector of the p53 pathway, but not several other p53 target genes. Nup98 regulates p21 mRNA levels by a posttranscriptional mechanism in which a complex containing Nup98 and the p21 mRNA 3'UTR protects p21 mRNA from degradation by the exosome. An in silico approach revealed another p53 target (14-3-3σ) to be similarly regulated by Nup98. The expression of Nup98 is reduced in murine and human hepatocellular carcinomas (HCCs) and correlates with p21 expression in HCC patients. Our study elucidates a previously unrecognized function of wild-type Nup98 in regulating select p53 target genes that is distinct from the well-characterized oncogenic properties of Nup98 fusion proteins.
p53 肿瘤抑制因子利用多种机制有选择性地调控其众多靶基因，而这些靶基因又反过来介导多种细胞过程。在这里，我们使用常规和单分子 mRNA 分析方法，证明核孔蛋白 Nup98 对于 p53 通路的关键效应因子 p21 的完全表达是必需的，但对于其他几个 p53 靶基因则不是必需的。Nup98 通过一种转录后机制来调节 p21 mRNA 的水平，其中包含 Nup98 和 p21 mRNA 3'UTR 的复合物保护 p21 mRNA 免受外切体的降解。一种计算机模拟方法揭示了另一个 p53 靶基因（14-3-3σ）也受到 Nup98 的类似调控。在鼠和人肝细胞癌（HCC）中，Nup98 的表达减少，并且与 HCC 患者中的 p21 表达相关。我们的研究阐明了野生型 Nup98 在调节某些 p53 靶基因方面的一个以前未被认识的功能，这与 Nup98 融合蛋白的特征性致癌特性是不同的。
