Chang Tsung-Cheng, Wentzel Erik A, Kent Oliver A, Ramachandran Kalyani, Mullendore Michael, Lee Kwang Hyuck, Feldmann Georg, Yamakuchi Munekazu, Ferlito Marcella, Lowenstein Charles J, Arking Dan E, Beer Michael A, Maitra Anirban, Mendell Joshua T
The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Mol Cell. 2007 Jun 8;26(5):745-52. doi: 10.1016/j.molcel.2007.05.010. Epub 2007 May 31.
The p53 tumor suppressor protein is a critical regulator of the cellular response to cancer-initiating insults such as genotoxic stress. In this report, we demonstrate that microRNAs (miRNAs) are important components of the p53 transcriptional network. Global miRNA expression analyses identified a cohort of miRNAs that exhibit p53-dependent upregulation following DNA damage. One such miRNA, miR-34a, is commonly deleted in human cancers and, as shown here, frequently absent in pancreatic cancer cells. Characterization of the miR-34a primary transcript and promoter demonstrates that this miRNA is directly transactivated by p53. Expression of miR-34a causes dramatic reprogramming of gene expression and promotes apoptosis. Much like the known set of p53-regulated genes, miR-34a-responsive genes are highly enriched for those that regulate cell-cycle progression, apoptosis, DNA repair, and angiogenesis. Therefore, it is likely that an important function of miR-34a is the modulation and fine-tuning of the gene expression program initiated by p53.
p53肿瘤抑制蛋白是细胞对致癌性损伤（如基因毒性应激）反应的关键调节因子。在本报告中，我们证明了微小RNA（miRNA）是p53转录网络的重要组成部分。全基因组miRNA表达分析鉴定出一组在DNA损伤后呈现p53依赖性上调的miRNA。其中一个这样的miRNA，即miR-34a，在人类癌症中常被缺失，并且如本文所示，在胰腺癌细胞中也经常缺失。对miR-34a初级转录本和启动子的表征表明，该miRNA直接由p53反式激活。miR-34a的表达导致基因表达的显著重编程并促进细胞凋亡。与已知的一组p53调节基因非常相似，miR-34a反应性基因高度富集于那些调节细胞周期进程、细胞凋亡、DNA修复和血管生成的基因。因此，miR-34a的一个重要功能可能是对由p53启动的基因表达程序进行调节和微调。
