p53 Regulates the Expression of LRP1 and Apoptosis through a Stress Intensity-Dependent MicroRNA Feedback Loop

Abstract

Summary: 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. : Leslie et al. uncover a p53-dependent feedback loop whereby p53-regulated protein-coding genes are inhibited by p53-regulated microRNAs in a stress intensity-dependent manner, resulting in increased cell death. The findings provide insight into how p53 controls the expression of its target genes to induce a pro-survival or pro-death response to stress. Keywords: p53, LRP1, miRNA, cancer, gene regulation, cell cycle arrest, apoptosis