miR-605 joins p53 network to form a p53:miR-605:Mdm2 positive feedback loop in response to stress

In cancers with wild-type (WT) p53 status, the function of p53 is inhibited through direct interaction with Mdm2 oncoprotein, a negative feedback loop to limit the function of p53. In response to cellular stress, p53 escapes the p53:Mdm2 negative feedback to accumulate rapidly to induce cell cycle arrest and apoptosis. We demonstrate herein that an microRNA miR-605 is a new component in the p53 gene network, being transcriptionally activated by p53 and post-transcriptionally repressing Mdm2. Activation of p53 upregulated miR-605 via interacting with the promoter region of the gene. Overexpression of miR-605 directly decreased Mdm2 expression at the post-transcriptional level but indirectly increased the transcriptional activity of p53 on miR-34a via downregulating Mdm2; knockdown of miR-605 did the opposite. Mdm2 inhibitor upregulated expression of both miR-34a and miR-605, which was mitigated by p53 inhibitor. miR-605 preferentially induced apoptosis in WT p53-expressing cells, an effect abolished by p53 inhibition. These results indicate that miR-605 acts to interrupt p53:Mdm2 interaction to create a positive feedback loop aiding rapid accumulation of p53 to facilitate its function in response to stress.