Disruption of the 5S RNP-Mdm2 interaction significantly improves the erythroid defect in a mouse model for Diamond-Blackfan anemia.
Jaako, Pekka LU ; Debnath, Shubhranshu LU ; Olsson, Karin LU ; Zhang, Y ; Flygare, Johan LU ; Lindström, M S ; Bryder, David LU and Karlsson, Stefan LU
(2015)
In Leukemia
29(11).
p.2221-2229
- 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 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... (More)
- 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 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.Leukemia accepted article preview online, 19 May 2015. doi:10.1038/leu.2015.128. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/5448846
- author
- Jaako, Pekka
LU
; Debnath, Shubhranshu
LU
; Olsson, Karin
LU
; Zhang, Y
; Flygare, Johan
LU
; Lindström, M S
; Bryder, David
LU
and Karlsson, Stefan
LU
- organization
- publishing date
- 2015
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Leukemia
- volume
- 29
- issue
- 11
- pages
- 2221 - 2229
- publisher
- Nature Publishing Group
- external identifiers
-
- pmid:25987256
- wos:000364527400012
- scopus:84946496523
- pmid:25987256
- ISSN
- 1476-5551
- DOI
- 10.1038/leu.2015.128
- language
- English
- LU publication?
- yes
- id
- 68bbf8ea-579a-4f7e-a781-dd1c0b0dc886 (old id 5448846)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/25987256?dopt=Abstract
- date added to LUP
- 2016-04-01 09:55:59
- date last changed
- 2022-04-27 08:57:45
@article{68bbf8ea-579a-4f7e-a781-dd1c0b0dc886,
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 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.Leukemia accepted article preview online, 19 May 2015. doi:10.1038/leu.2015.128.}},
author = {{Jaako, Pekka and Debnath, Shubhranshu and Olsson, Karin and Zhang, Y and Flygare, Johan and Lindström, M S and Bryder, David and Karlsson, Stefan}},
issn = {{1476-5551}},
language = {{eng}},
number = {{11}},
pages = {{2221--2229}},
publisher = {{Nature Publishing Group}},
series = {{Leukemia}},
title = {{Disruption of the 5S RNP-Mdm2 interaction significantly improves the erythroid defect in a mouse model for Diamond-Blackfan anemia.}},
url = {{https://lup.lub.lu.se/search/files/1401027/8571889.pdf}},
doi = {{10.1038/leu.2015.128}},
volume = {{29}},
year = {{2015}},
}