Ribosomal protein S27-like is a physiological regulator of p53 that suppresses genomic instability and tumorigenesis
Abstract
Cell-based studies showed that several Mdm2-binding ribosomal proteins, upon overexpression, stabilize and activate p53. In contrast, here we show in a mouse knockout study that Mdm2-binding ribosomal protein S27-like (Rps27l), upon disruption, activates p53. Germline inactivation of Rps27l triggers ribosomal stress to stabilize Mdm2, which degrades Mdm4 to reduce Mdm2-Mdm4 E3 ligase towards p53, leading to p53-dependent apoptotic depletion of hematopoietic stem cells and postnatal death, which is rescued by Trp53 deletion. Paradoxically, while increased p53 is expected to inhibit tumorigenesis, Rps27l-/-;Trp53+/- mice develop lymphomas at higher incidence with p53 loss-of-heterozygosity and severe genome aneuploidy, suggesting that Rps27l disruption impose a selection pressure against p53. Thus, Rps27l has dual functions in p53 regulation: under Trp53+/+ background, Rps27l disruption triggers ribosomal stress to induce p53 and apoptosis, whereas under Trp53+/- background, Rps27l disruption triggers genomic instability and Trp53 deletion to promote tumorigenesis. Our study provides a new paradigm of p53 regulation.
Article and author information
Author details
Reviewing Editor
- Carol Prives, Columbia University, United States
Ethics
Animal experimentation: All the animal procedures were approved by the University of Michigan Committee on Use and Care of Animals (Protocol # PRO00004764). Animal care was provided in accordance with the principles and procedures outlined in the National Research Council Guide for the Care and Use of Laboratory Animals.
Version history
- Received: January 8, 2014
- Accepted: August 20, 2014
- Accepted Manuscript published: August 21, 2014 (version 1)
- Version of Record published: September 15, 2014 (version 2)
Copyright
© 2014, Xiong et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 2,919
- views
-
- 329
- downloads
-
- 40
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Cell Biology
Elastic cartilage constitutes a major component of the external ear, which functions to guide sound to the middle and inner ears. Defects in auricle development cause congenital microtia, which affects hearing and appearance in patients. Mutations in several genes have been implicated in microtia development, yet, the pathogenesis of this disorder remains incompletely understood. Here, we show that Prrx1 genetically marks auricular chondrocytes in adult mice. Interestingly, BMP-Smad1/5/9 signaling in chondrocytes is increasingly activated from the proximal to distal segments of the ear, which is associated with a decrease in chondrocyte regenerative activity. Ablation of Bmpr1a in auricular chondrocytes led to chondrocyte atrophy and microtia development at the distal part. Transcriptome analysis revealed that Bmpr1a deficiency caused a switch from the chondrogenic program to the osteogenic program, accompanied by enhanced protein kinase A activation, likely through increased expression of Adcy5/8. Inhibition of PKA blocked chondrocyte-to-osteoblast transformation and microtia development. Moreover, analysis of single-cell RNA-seq of human microtia samples uncovered enriched gene expression in the PKA pathway and chondrocyte-to-osteoblast transformation process. These findings suggest that auricle cartilage is actively maintained by BMP signaling, which maintains chondrocyte identity by suppressing osteogenic differentiation.
-
- Cancer Biology
- Cell Biology
Internalization from the cell membrane and endosomal trafficking of receptor tyrosine kinases (RTKs) are important regulators of signaling in normal cells that can frequently be disrupted in cancer. The adrenal tumor pheochromocytoma (PCC) can be caused by activating mutations of the rearranged during transfection (RET) receptor tyrosine kinase, or inactivation of TMEM127, a transmembrane tumor suppressor implicated in trafficking of endosomal cargos. However, the role of aberrant receptor trafficking in PCC is not well understood. Here, we show that loss of TMEM127 causes wildtype RET protein accumulation on the cell surface, where increased receptor density facilitates constitutive ligand-independent activity and downstream signaling, driving cell proliferation. Loss of TMEM127 altered normal cell membrane organization and recruitment and stabilization of membrane protein complexes, impaired assembly, and maturation of clathrin-coated pits, and reduced internalization and degradation of cell surface RET. In addition to RTKs, TMEM127 depletion also promoted surface accumulation of several other transmembrane proteins, suggesting it may cause global defects in surface protein activity and function. Together, our data identify TMEM127 as an important determinant of membrane organization including membrane protein diffusability and protein complex assembly and provide a novel paradigm for oncogenesis in PCC where altered membrane dynamics promotes cell surface accumulation and constitutive activity of growth factor receptors to drive aberrant signaling and promote transformation.