Authors: Chang TC; Wentzel EA; Kent OA; Ramachandran K; Mullendore M; Lee KH; Feldmann G; Yamakuchi M; Ferlito M; Lowenstein CJ; Arking DE; Beer MA; Maitra A; Mendell JT
Abstract: 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.
Keywords: Apoptosis/*genetics/*physiology; Base Sequence; Cell Line, Tumor; DNA Damage; *Gene Expression; Humans; MicroRNAs/*genetics/*metabolism; Pancreatic Neoplasms/genetics/metabolism; Promoter Regions, Genetic; RNA, Neoplasm/genetics/metabolism; *Transcriptional Activation; Tumor Suppressor Protein p53/*metabolism|
Journal: Molecular cell Volume: 26 Issue: 5 Pages: 745-52 Date: June 2, 2007 PMID: 17540599 |
Chang TC, Wentzel EA, Kent OA, Ramachandran K, Mullendore M, Lee KH, Feldmann G, Yamakuchi M, Ferlito M, Lowenstein CJ, Arking DE, Beer MA, Maitra A, Mendell JT (2007) Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Molecular cell 26: 745-52.
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