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Ribosomal protein S19 deficiency in zebrafish leads to developmental abnormalities and defective erythropoiesis through activation of p53 protein family

Danilova, Nadia and Sakamoto, Kathleen M. and Lin, Shuo (2008) Ribosomal protein S19 deficiency in zebrafish leads to developmental abnormalities and defective erythropoiesis through activation of p53 protein family. Blood, 112 (13). pp. 5228-5237. ISSN 0006-4971. http://resolver.caltech.edu/CaltechAUTHORS:DANblo08

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Image (JPEG) (Figure S1. In contrast to erythropoiesis, development of myeloid and lymphoid lineages is less affected in RPS19-deficient zebrafish) - Supplemental Material
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Image (JPEG) (Figure S2. Expression of p53 family genes in embryos with mutations in ribosomal proteins S8, S11, and S18) - Supplemental Material
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Image (JPEG) (Figure S3. p53−/− zebrafish embryos injected with RPS19 morpholinos had no obvious morphological defects) - Supplemental Material
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Abstract

Mutations in several ribosomal proteins (RPs) lead to Diamond-Blackfan anemia (DBA), a syndrome characterized by defective erythropoiesis, congenital anomalies, and increased frequency of cancer. RPS19 is the most frequently mutated RP in DBA. RPS19 deficiency impairs ribosomal biogenesis, but how this leads to DBA or cancer remains unknown. We have found that rps19 deficiency in ze-brafish results in hematopoietic and developmental abnormalities resembling DBA. Our data suggest that the rps19-deficient phenotype is mediated by dysregulation of deltaNp63 and p53. During gastrulation, deltaNp63 is required for specification of nonneural ectoderm and its up-regulation suppresses neural differentiation, thus contributing to brain/craniofacial defects. In rps19-deficient embryos, deltaNp63 is induced in erythroid progenitors and may contribute to blood defects. We have shown that suppression of p53 and deltaNp63 alleviates the rps19-deficient phenotypes. Mutations in other ribosomal proteins, such as S8, S11, and S18, also lead to up-regulation of p53 pathway, suggesting it is a common response to ribosomal protein deficiency. Our finding provides new insights into pathogenesis of DBA. Ribosomal stress syndromes represent a broader spectrum of human congenital diseases caused by genotoxic stress; therefore, imbalance of p53 family members may become a new target for therapeutics.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1182/blood-2008-01-132290DOIArticle
http://bloodjournal.hematologylibrary.org/cgi/content/abstract/112/13/5228PublisherArticle
ORCID:
AuthorORCID
Sakamoto, Kathleen M.0000-0003-0494-8838
Additional Information:© 2008 American Society of Hematology. Submitted January 6, 2008; accepted April 5, 2008. Prepublished online as Blood First Edition paper, May 30, 2008; DOI 10.1182/blood-2008-01-132290. The authors thank A. Amsterdam for providing the RP mutants embryos, J. Werk for help with the hemoglobin assay, N. Federman for critical review, and members of S.L.'s laboratory for helpful discussions and reagents. This study was supported by the Diamond Blackfan Anemia Foundation. Contribution: N.D. designed and performed research, analyzed data, and wrote the paper; and K.M.S. and S.L. designed research, analyzed data and wrote the paper. The authors declare no competing financial interests. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 USC section 1734. The online version of this article contains a data supplement.
Funders:
Funding AgencyGrant Number
Diamond Blackfan Anemia FoundationUNSPECIFIED
Issue or Number:13
Record Number:CaltechAUTHORS:DANblo08
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:DANblo08
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:12523
Collection:CaltechAUTHORS
Deposited By: Archive Administrator
Deposited On:12 Dec 2008 07:13
Last Modified:19 Apr 2017 23:27

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