Transactivation of miR-34a by p53 Broadly Influences Gene Expression and Promotes Apoptosis

Mol Cell. 2007 Jun 8;26(5):745-52. doi: 10.1016/j.molcel.2007.05.010. Epub 2007 May 31.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / genetics*
  • Apoptosis / physiology*
  • Base Sequence
  • Cell Line, Tumor
  • DNA Damage
  • Gene Expression*
  • Humans
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism
  • Promoter Regions, Genetic
  • RNA, Neoplasm / genetics
  • RNA, Neoplasm / metabolism
  • Transcriptional Activation*
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • MicroRNAs
  • RNA, Neoplasm
  • TP53 protein, human
  • Tumor Suppressor Protein p53