title: 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.
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, United States.
authors.forename: Xiufang
authors.initials: X
authors.lastname: Xiong
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, United States.
authors.forename: Yongchao
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Center for Cancer and Immunology Research, Children's National Medical Center, Washington, United States.
authors.forename: Fei
authors.initials: F
authors.lastname: Tang
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, United States.
authors.forename: Dongping
authors.initials: D
authors.lastname: Wei
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, United States.
authors.forename: Daffyd
authors.initials: D
authors.lastname: Thomas
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, United States.
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Center for Cancer and Immunology Research, Children's National Medical Center, Washington, United States.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Center for Cancer and Immunology Research, Children's National Medical Center, Washington, United States.
authors.forename: Pan
authors.initials: P
authors.lastname: Zheng
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, United States.
authors.forename: Yi
authors.initials: Y
authors.lastname: Sun
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability / Q000235:genetics*; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D059748:Proteolysis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012269:Ribosomal Proteins / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
chemical_list: C461497:Mdm4 protein, mouse; D011518:Proto-Oncogene Proteins; D012269:Ribosomal Proteins; C000598878:Rps27l protein, mouse; D016159:Tumor Suppressor Protein p53; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases
keywords: Mdm2-Mdm4; aneuploidy; cell biology; developmental biology; human; mouse; mouse knockout; p53; ribosomal proteins; stem cells; tumorigenesis