p53 Regulates the Expression of LRP1 and Apoptosis through a Stress Intensity-Dependent MicroRNA Feedback Loop
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 respon...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2018-08-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124718310878 |
| _version_ | 1819051790722662400 |
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| author | Patrick L. Leslie Derek A. Franklin Yong Liu Yanping Zhang |
| author_facet | Patrick L. Leslie Derek A. Franklin Yong Liu Yanping Zhang |
| author_sort | Patrick L. Leslie |
| collection | DOAJ |
| description | 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 |
| first_indexed | 2024-12-21T12:09:33Z |
| format | Article |
| id | doaj.art-d8f538c3505b40dfb8acf567669a0699 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-21T12:09:33Z |
| publishDate | 2018-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-d8f538c3505b40dfb8acf567669a06992022-12-21T19:04:37ZengElsevierCell Reports2211-12472018-08-0124614841495p53 Regulates the Expression of LRP1 and Apoptosis through a Stress Intensity-Dependent MicroRNA Feedback LoopPatrick L. Leslie0Derek A. Franklin1Yong Liu2Yanping Zhang3Department of Radiation Oncology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461, USA; Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461, USADepartment of Radiation Oncology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461, USA; Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461, USADepartment of Radiation Oncology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461, USA; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical College, Xuzhou, Jiangsu 221002, ChinaDepartment of Radiation Oncology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461, USA; Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461, USA; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical College, Xuzhou, Jiangsu 221002, China; Corresponding authorSummary: 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, apoptosishttp://www.sciencedirect.com/science/article/pii/S2211124718310878 |
| spellingShingle | Patrick L. Leslie Derek A. Franklin Yong Liu Yanping Zhang p53 Regulates the Expression of LRP1 and Apoptosis through a Stress Intensity-Dependent MicroRNA Feedback Loop Cell Reports |
| title | p53 Regulates the Expression of LRP1 and Apoptosis through a Stress Intensity-Dependent MicroRNA Feedback Loop |
| title_full | p53 Regulates the Expression of LRP1 and Apoptosis through a Stress Intensity-Dependent MicroRNA Feedback Loop |
| title_fullStr | p53 Regulates the Expression of LRP1 and Apoptosis through a Stress Intensity-Dependent MicroRNA Feedback Loop |
| title_full_unstemmed | p53 Regulates the Expression of LRP1 and Apoptosis through a Stress Intensity-Dependent MicroRNA Feedback Loop |
| title_short | p53 Regulates the Expression of LRP1 and Apoptosis through a Stress Intensity-Dependent MicroRNA Feedback Loop |
| title_sort | p53 regulates the expression of lrp1 and apoptosis through a stress intensity dependent microrna feedback loop |
| url | http://www.sciencedirect.com/science/article/pii/S2211124718310878 |
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