| Haploinsufficiency for ribosomal protein genes causes selective activation of p53 in human erythroid progenitor cells. | |
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MedLine Citation:
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PMID: 21068437 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Haploinsufficiency for ribosomal protein genes has been implicated in the pathophysiology of Diamond-Blackfan anemia (DBA) and the 5q-syndrome, a subtype of myelodysplastic syndrome. The p53 pathway is activated by ribosome dysfunction, but the molecular basis for selective impairment of the erythroid lineage in disorders of ribosome function has not been determined. We found that p53 accumulates selectively in the erythroid lineage in primary human hematopoietic progenitor cells after expression of shRNAs targeting RPS14, the ribosomal protein gene deleted in the 5q-syndrome, or RPS19, the most commonly mutated gene in DBA. Induction of p53 led to lineage-specific accumulation of p21 and consequent cell cycle arrest in erythroid progenitor cells. Pharmacologic inhibition of p53 rescued the erythroid defect, whereas nutlin-3, a compound that activates p53 through inhibition of HDM2, selectively impaired erythropoiesis. In bone marrow biopsies from patients with DBA or del(5q) myelodysplastic syndrome, we found an accumulation of nuclear p53 staining in erythroid progenitor cells that was not present in control samples. Our findings indicate that the erythroid lineage has a low threshold for the induction of p53, providing a basis for the failure of erythropoiesis in the 5q-syndrome, DBA, and perhaps other bone marrow failure syndromes. |
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Authors:
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Shilpee Dutt; Anupama Narla; Katherine Lin; Ann Mullally; Nirmalee Abayasekara; Christine Megerdichian; Frederick H Wilson; Treeve Currie; Arati Khanna-Gupta; Nancy Berliner; Jeffery L Kutok; Benjamin L Ebert |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-11-10 |
Journal Detail:
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Title: Blood Volume: 117 ISSN: 1528-0020 ISO Abbreviation: Blood Publication Date: 2011 Mar |
Date Detail:
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Created Date: 2011-03-04 Completed Date: 2011-05-09 Revised Date: 2012-05-15 |
Medline Journal Info:
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Nlm Unique ID: 7603509 Medline TA: Blood Country: United States |
Other Details:
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Languages: eng Pagination: 2567-76 Citation Subset: AIM; IM |
Copyright Information:
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© 2011 by The American Society of Hematology |
Affiliation:
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Division of Hematology, Brigham and Women's Hospital, Boston, MA, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Anemia, Diamond-Blackfan
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genetics,
pathology Anemia, Macrocytic / genetics, pathology Animals Benzothiazoles / pharmacology Cell Cycle / drug effects Cell Lineage / drug effects Cell Nucleolus / drug effects, metabolism Chromosome Deletion Chromosomes, Human, Pair 5 / genetics Cyclin-Dependent Kinase Inhibitor p21 / metabolism Erythroid Precursor Cells / drug effects, metabolism*, pathology Haploinsufficiency / genetics* Hematopoiesis / drug effects Humans Imidazoles / metabolism Mice Mice, Inbred BALB C Myelodysplastic Syndromes / genetics, pathology Piperazines / metabolism Protein Binding / drug effects Proto-Oncogene Proteins c-mdm2 / metabolism RNA, Small Interfering / metabolism Ribosomal Proteins / deficiency, genetics*, metabolism Toluene / analogs & derivatives, pharmacology Tumor Suppressor Protein p53 / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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5R01 HL082945/HL/NHLBI NIH HHS; P01 CA108631/CA/NCI NIH HHS; R01 HL082945/HL/NHLBI NIH HHS; R01 HL082945-06/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Benzothiazoles; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Imidazoles; 0/Piperazines; 0/RNA, Small Interfering; 0/Ribosomal Proteins; 0/Tumor Suppressor Protein p53; 0/nutlin 3; 0/pifithrin; 0/ribosomal protein L11; 0/ribosomal protein S14; 0/ribosomal protein S19; 108-88-3/Toluene; EC 6.3.2.19/MDM2 protein, human; EC 6.3.2.19/Proto-Oncogene Proteins c-mdm2 |
| Comments/Corrections | |
Comment In:
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Blood. 2011 Mar 3;117(9):2558-9
[PMID:
21372157
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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