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Gene. 2014 Jul 25;545(2):282-9. doi: 10.1016/j.gene.2014.04.077. Epub 2014 May 15.

Dissecting the transcriptional phenotype of ribosomal protein deficiency: implications for Diamond-Blackfan Anemia.

Author information

1
Department of Health Sciences, University of Eastern Piedmont, Novara, Italy.
2
Department of Sciences and Technological Innovation, University of Eastern Piedmont, Alessandria, Italy.
3
Department of Chemistry, University of Milan, Italy.
4
U1009, AP-HP, Service d'Hématologie Biologique, Hôpital Robert Debré, Université Paris VII-Denis Diderot, Sorbonne Paris Cité, F-75475 Paris, France.
5
New York Blood Center, NY, USA.
6
International School for Advanced Studies (SISSA/ISAS), Trieste, Italy.
7
Department of Pediatric Sciences, University of Torino, Torino, Italy.
8
Department of Biotechnologies and Biosciences, Milano-Bicocca University, Italy.
9
University of Louisville, KY, USA.
10
Department of Health Sciences, University of Eastern Piedmont, Novara, Italy. Electronic address: irma.dianzani@med.unipmn.it.

Abstract

Defects in genes encoding ribosomal proteins cause Diamond Blackfan Anemia (DBA), a red cell aplasia often associated with physical abnormalities. Other bone marrow failure syndromes have been attributed to defects in ribosomal components but the link between erythropoiesis and the ribosome remains to be fully defined. Several lines of evidence suggest that defects in ribosome synthesis lead to "ribosomal stress" with p53 activation and either cell cycle arrest or induction of apoptosis. Pathways independent of p53 have also been proposed to play a role in DBA pathogenesis. We took an unbiased approach to identify p53-independent pathways activated by defects in ribosome synthesis by analyzing global gene expression in various cellular models of DBA. Ranking-Principal Component Analysis (Ranking-PCA) was applied to the identified datasets to determine whether there are common sets of genes whose expression is altered in these different cellular models. We observed consistent changes in the expression of genes involved in cellular amino acid metabolic process, negative regulation of cell proliferation and cell redox homeostasis. These data indicate that cells respond to defects in ribosome synthesis by changing the level of expression of a limited subset of genes involved in critical cellular processes. Moreover, our data support a role for p53-independent pathways in the pathophysiology of DBA.

KEYWORDS:

Bone marrow failure; Diamond Blackfan Anemia; Ribosomal protein; Ribosomopathy

PMID:
24835311
PMCID:
PMC4058751
DOI:
10.1016/j.gene.2014.04.077
[Indexed for MEDLINE]
Free PMC Article

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