title: Disruption of the 5S RNP-Mdm2 interaction significantly improves the erythroid defect in a mouse model for Diamond-Blackfan anemia.
abstract: Diamond-Blackfan anemia (DBA) is a congenital erythroid hypoplasia caused by haploinsufficiency of genes encoding ribosomal proteins (RPs). Perturbed ribosome biogenesis in DBA has been shown to induce a p53-mediated ribosomal stress response. However, the mechanisms of p53 activation and its relevance for the erythroid defect remain elusive. Previous studies have indicated that activation of p53 is caused by the inhibition of mouse double minute 2 (Mdm2), the main negative regulator of p53, by the 5S ribonucleoprotein particle (RNP). Meanwhile, it is not clear whether this mechanism solely mediates the p53-dependent component found in DBA. To approach this question, we crossed our mouse model for RPS19-deficient DBA with Mdm2(C305F) knock-in mice that have a disrupted 5S RNP-Mdm2 interaction. Upon induction of the Rps19 deficiency, Mdm2(C305F) reversed the p53 response and improved expansion of hematopoietic progenitors in vitro, and ameliorated the anemia in vivo. Unexpectedly, disruption of the 5S RNP-Mdm2 interaction also led to selective defect in erythropoiesis. Our findings highlight the sensitivity of erythroid progenitor cells to aberrations in p53 homeostasis mediated by the 5S RNP-Mdm2 interaction. Finally, we provide evidence indicating that physiological activation of the 5S RNP-Mdm2-p53 pathway may contribute to functional decline of the hematopoietic system in a cell-autonomous manner over time.
authors.affiliation: Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden.|Molecular Hematology, Lund Stem Cell Center, Lund University, Lund, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Jaako
authors.affiliation: Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Debnath
authors.affiliation: Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Olsson
authors.affiliation: Department of Radiation Oncology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Flygare
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: M S
authors.initials: MS
authors.lastname: Lindström
authors.affiliation: Molecular Hematology, Lund Stem Cell Center, Lund University, Lund, Sweden.
authors.forename: D
authors.initials: D
authors.lastname: Bryder
authors.affiliation: Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Karlsson
mesh_terms: D029503:Anemia, Diamond-Blackfan / Q000209:etiology*; D000818:Animals; D004195:Disease Models, Animal; D004318:Doxycycline / Q000494:pharmacology; D015672:Erythroid Precursor Cells / Q000502:physiology*; D004920:Erythropoiesis; D051379:Mice; D008810:Mice, Inbred C57BL; D051736:Proto-Oncogene Proteins c-mdm2 / Q000502:physiology*; D012341:RNA, Ribosomal, 5S / Q000502:physiology; D012261:Ribonucleoproteins / Q000502:physiology*; D012269:Ribosomal Proteins / Q000502:physiology; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: D012341:RNA, Ribosomal, 5S; D012261:Ribonucleoproteins; D012269:Ribosomal Proteins; C531064:Rps19 protein, mouse; D016159:Tumor Suppressor Protein p53; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D004318:Doxycycline