Ribosomal protein S27-like is a physiological regulator of p53 that suppresses genomic instability and tumorigenesis
Xiufang Xiong,
Yongchao Zhao,
Fei Tang,
Dongping Wei,
Daffyd Thomas,
Xiang Wang,
Yang Liu,
Pan Zheng,
Yi Sun
Affiliations
Xiufang Xiong
Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, United States
Yongchao Zhao
Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, United States
Fei Tang
Center for Cancer and Immunology Research, Children's National Medical Center, Washington, United States
Dongping Wei
Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, United States
Daffyd Thomas
Department of Pathology, University of Michigan Medical School, Ann Arbor, United States; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, United States
Xiang Wang
Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, United States
Yang Liu
Center for Cancer and Immunology Research, Children's National Medical Center, Washington, United States
Pan Zheng
Center for Cancer and Immunology Research, Children's National Medical Center, Washington, United States
Yi Sun
Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, United States; Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
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.
