Differential regulation of microRNAs by p53 revealed by massively parallel Sequencing -: miR-34a is a p53 target that induces apoptosis and G1-arrest

In a genome- wide screen for microRNAs regulated by the transcription factor encoded by the p53 tumor suppressor gene we found that after p53- activation the abundance of thirty- four miRNAs was significantly increased, whereas sixteen miRNAs were suppressed. The induction of miR- 34a was most pronounced among all differential regulations. Also expression of the primary miR- 34a transcript was induced after p53 activation and by DNA damage in a p53- dependent manner. p53 occupied an evolutionarily conserved binding site proximal to the first non- coding exon of miR- 34a. Ectopic miR- 34a induced apoptosis and a cell cycle arrest in the G1- phase, thereby suppressing tumor cell proliferation. Other p53- induced miRNAs identified here may also have tumor suppressive potential as they are known to suppress the anti- apoptotic factor Bcl2 ( miR- 15a/ 16) and the oncogenes RAS and HMGA2 ( let- 7a). Our results for the first time directly integrate the regulation of miRNA expression into the transcriptional network regulated by p53. siRNAs corresponding to p53- induced miRNAs may have potential as cancer therapeutic agents as RNA interference based therapies are currently emerging.