title: TNF-mediated inflammation represses GATA1 and activates p38 MAP kinase in RPS19-deficient hematopoietic progenitors.
abstract: Diamond-Blackfan anemia (DBA) is an inherited disorder characterized by defects in erythropoiesis, congenital abnormalities, and predisposition to cancer. Approximately 25% of DBA patients have a mutation in RPS19, which encodes a component of the 40S ribosomal subunit. Upregulation of p53 contributes to the pathogenesis of DBA, but the link between ribosomal protein mutations and erythropoietic defects is not well understood. We found that RPS19 deficiency in hematopoietic progenitor cells leads to decreased GATA1 expression in the erythroid progenitor population and p53-dependent upregulation of tumor necrosis factor-α (TNF-α) in nonerythroid cells. The decrease in GATA1 expression was mediated, at least in part, by activation of p38 MAPK in erythroid cells and rescued by inhibition of TNF-α or p53. The anemia phenotype in rps19-deficient zebrafish was reversed by treatment with the TNF-α inhibitor etanercept. Our data reveal that RPS19 deficiency leads to inflammation, p53-dependent increase in TNF-α, activation of p38 MAPK, and decreased GATA1 expression, suggesting a novel mechanism for the erythroid defects observed in DBA.
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA; and.
authors.forename: Elena
authors.initials: E
authors.lastname: Bibikova
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA; and.
authors.forename: Min-Young
authors.initials: MY
authors.lastname: Youn
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA.
authors.forename: Nadia
authors.initials: N
authors.lastname: Danilova
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA; and.
authors.forename: Yukako
authors.initials: Y
authors.lastname: Ono-Uruga
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA; and.
authors.forename: Yoan
authors.initials: Y
authors.lastname: Konto-Ghiorghi
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA; and.
authors.forename: Rachel
authors.initials: R
authors.lastname: Ochoa
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA; and.
authors.forename: Anupama
authors.initials: A
authors.lastname: Narla
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA; and.
authors.forename: Bertil
authors.initials: B
authors.lastname: Glader
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA.
authors.forename: Shuo
authors.initials: S
authors.lastname: Lin
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA; and.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Sakamoto
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004625:Embryo, Nonmammalian / Q000196:embryology / Q000378:metabolism; D004789:Enzyme Activation; D041905:Erythroid Cells / Q000378:metabolism; D004920:Erythropoiesis / Q000187:drug effects / Q000235:genetics; D000068800:Etanercept; D050982:GATA1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D018124:Receptors, Tumor Necrosis Factor; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D050982:GATA1 Transcription Factor; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D012269:Ribosomal Proteins; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; C040343:ribosomal protein S19; D048051:p38 Mitogen-Activated Protein Kinases; D000068800:Etanercept