Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis.
Journal: 2007/July - Molecular Cell
ISSN: 1097-2765
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.
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Mol Cell 26(5): 745-752

Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis

+5 authors
The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
*Correspondence: ude.imhj@llednemj (J.T.M.); phone: 410-502-0428, fax: 410-502-1853
These authors contributed equally to this work
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SUMMARY

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 finetuning of the gene expression program initiated by p53.

SUMMARY

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