Understanding how p53 activates certain gene programs and not others is critical. Here, we identify low-density lipoprotein receptor-related protein 1 (LRP1), a transmembrane endocytic receptor, as a p53 target gene. We show that, although LRP1 transcript expression is upregulated in response to both sub-lethal and lethal doses of p53-activating stress, LRP1 protein is only upregulated in response to sub-lethal stress. Interestingly, lethal doses of p53-activating stress inhibit LRP1 de novo translation through an miRNA-based translational repression mechanism. We show that the p53-regulated miRNAs miR-103 and miR-107 are significantly upregulated by lethal doses of stress, resulting in suppression of LRP1 translation and cell death. Our results define a negative feedback loop involving the p53-regulated coding gene LRP1 and p53-regulated miRNA genes. These findings provide mechanistic insight into the selective expression of p53 target genes in response to different stress intensities to elicit either cell survival or cell death.
Keywords: LRP1; apoptosis; cancer; cell cycle arrest; gene regulation; miRNA; p53.
Copyright © 2018. Published by Elsevier Inc.