Transcriptional Activation of miR-34a Contributes to p53-mediated Apoptosis

Mol Cell. 2007 Jun 8;26(5):731-43. doi: 10.1016/j.molcel.2007.05.017. Epub 2007 May 31.

Abstract

p53 is a potent tumor suppressor, whose biological effects are largely due to its function as a transcriptional regulator. Here we report that, in addition to regulating the expression of hundreds of protein-coding genes, p53 also modulates the levels of microRNAs (miRNAs). Specifically, p53 can induce expression of microRNA-34a (miR-34a) in cultured cells as well as in irradiated mice, by binding to a perfect p53 binding site located within the gene that gives rise to miR-34a. Processing of the primary transcript into mature miR-34a involves the excision of a 30 kb intron. Notably, inactivation of miR-34a strongly attenuates p53-mediated apoptosis in cells exposed to genotoxic stress, whereas overexpression of miR-34a mildly increases apoptosis. Hence, miR-34a is a direct proapoptotic transcriptional target of p53 that can mediate some of p53's biological effects. Perturbation of miR-34a expression, as occurs in some human cancers, may thus contribute to tumorigenesis by attenuating p53-dependent apoptosis.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis / genetics*
  • Apoptosis / physiology*
  • Base Sequence
  • Cell Line, Tumor
  • Expressed Sequence Tags
  • Genes, p53
  • Humans
  • In Vitro Techniques
  • Mice
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism*
  • Molecular Sequence Data
  • Mutation
  • Promoter Regions, Genetic
  • RNA Splicing
  • RNA, Neoplasm / genetics
  • RNA, Neoplasm / metabolism
  • Temperature
  • Transcriptional Activation*
  • Transfection
  • Tumor Suppressor Protein p53 / deficiency
  • Tumor Suppressor Protein p53 / metabolism*

Substances

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