p16 Controls p53 Protein Expression Through miR-dependent Destabilization of MDM2.

p16 and p53 are two major tumor suppressor proteins that are both upregulated in response to various cellular stresses and during senescence and aging. p53 is a well-characterized transcription factor, while p16 a cyclin-dependent kinase inhibitor encoded by the gene, and controls the expression of several genes through protein-protein interactions and also via miRNAs. This report demonstrates a p16-dependent positive regulation of p53 expression, at the protein level, in various human cells as well as in mouse embryonic fibroblasts. p16 suppresses p53 turnover through inhibition of its MDM2-related ubiquitination. This effect occurs through p16-related promotion of the mRNA turnover via the p16 downstream effectors miR-141 and miR-146b-5p, which bind specific sites at the 3' untranslated region of the mRNA. The current findings show p16-dependent stabilization of p53 through miR-141/miR-146b-5p-related posttranscriptional repression of MDM2, thus providing new insights into the complex functional link between p16 and p53. .