MiR-34, SIRT1 and p53: The feedback loop

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression. Several studies have linked dysregulation of miRNA with tumorigenesis. The TP53 is one of the most commonly mutated genes in human cancers, and its gene product p53 activates transcription of a set of miRNA including the miR-34 family of miRNA. The miR-34 family regulates cell cycle progression, cellular senescence and apoptosis, but the targets of miR-34 are not completely defined. We recently found that miR-34a inhibits SIRT1, a gene that regulates cellular senescence and limits longevity. SIRT1 also regulates p53 dependent apoptosis through deacetylating and stabilizing p53. We also discovered that SIRT1 mediates miR-34a activation of apoptosis by regulating p53 activity. Based on this observation, we propose a positive feedback loop, in which p53 induces expression of miR-34a which suppresses SIRT1, increasing p53 activity.