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Medline ® Abstract for Reference 77

of 'Molecular pathogenesis of exocrine pancreatic cancer'

77
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Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis.
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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
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Mol Cell. 2007;26(5):745. 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.
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The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
PMID