PUBLICATION
TNF-mediated inflammation represses GATA1 and activates p38 MAP kinase in RPS19-deficient hematopoietic progenitors
- Authors
- Bibikova, E., Youn, M.Y., Danilova, N., Ono-Uruga, Y., Konto-Ghiorghi, Y., Ochoa, R., Narla, A., Glader, B., Lin, S., Sakamoto, K.M.
- ID
- ZDB-PUB-141002-3
- Date
- 2014
- Source
- Blood 124(25): 3791-8 (Journal)
- Registered Authors
- Danilova, Nadia, Lin, Shuo
- Keywords
- none
- MeSH Terms
-
- Animals
- Blotting, Western
- Cells, Cultured
- Embryo, Nonmammalian/embryology
- Embryo, Nonmammalian/metabolism
- Enzyme Activation
- Erythroid Cells/metabolism
- Erythropoiesis/drug effects
- Erythropoiesis/genetics
- Etanercept
- GATA1 Transcription Factor/genetics
- GATA1 Transcription Factor/metabolism*
- Gene Expression
- Hematopoietic Stem Cells/metabolism*
- Humans
- Immunoglobulin G/pharmacology
- Inflammation/genetics
- Inflammation/metabolism*
- RNA Interference
- Receptors, Tumor Necrosis Factor
- Reverse Transcriptase Polymerase Chain Reaction
- Ribosomal Proteins/genetics
- Ribosomal Proteins/metabolism*
- Tumor Necrosis Factor-alpha/genetics
- Tumor Necrosis Factor-alpha/metabolism*
- Tumor Suppressor Protein p53/genetics
- Tumor Suppressor Protein p53/metabolism
- Zebrafish/embryology
- Zebrafish/genetics
- Zebrafish/metabolism
- p38 Mitogen-Activated Protein Kinases/genetics
- p38 Mitogen-Activated Protein Kinases/metabolism*
- PubMed
- 25270909 Full text @ Blood
Citation
Bibikova, E., Youn, M.Y., Danilova, N., Ono-Uruga, Y., Konto-Ghiorghi, Y., Ochoa, R., Narla, A., Glader, B., Lin, S., Sakamoto, K.M. (2014) TNF-mediated inflammation represses GATA1 and activates p38 MAP kinase in RPS19-deficient hematopoietic progenitors. Blood. 124(25):3791-8.
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 TNF-α in non-erythroid 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping