Abstract
p16INK4A 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 p16INK4A a cyclin-dependent kinase inhibitor encoded by the CDKN2A gene, and controls the expression of several genes through protein-protein interactions and also via miRNAs. This report demonstrates a p16INK4A-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 MDM2 mRNA turnover via the p16INK4A downstream effectors miR-141 and miR-146b-5p, which bind specific sites at the 3' untranslated region of the MDM2 mRNA.Implications: The current findings show p16INK4A-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 p16INK4A and p53. Mol Cancer Res; 16(8); 1299-308. ©2018 AACR.
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