Model of miR-34a and p53 interactions.

Abstract

<p>Competing negative and positive feedback loops determine the net effect of miR-34a on p53 function. Highlighted in red are the new layers of regulation revealed by our data. Activation of p53 by cellular stress leads to transcription of miR-34 miRNAs, which in turn can enhance p53 function by: (1) miR-34a-mediated inhibition of multiple negative regulators of p53 to further increase p53 transcriptional activity; and (2) miR-34a-mediated increase of p53 protein stability (miR-34a feed-forward loops); or inhibit p53 function by: (3) direct miR-34a-mediated inhibition of <i>TP53</i>; and (4) direct miR-34 inhibition of many p53-activated genes (negative feedback loops). The mechanism by which miR-34a increases p53 half-life is not known, but its suppression of <i>YY1</i>, whose gene product is known to enhance p53-MDM2 interactions may contribute. The net effect of miR-34a on the p53 response will depend on the relative importance of these pathways, which will be determined by differences in gene expression in each cell.</p