Published online 2 September 2008
Haematologica, Vol 93, Issue 11, 1627-1634 doi:10.3324/haematol.13023
Copyright © 2008 by Ferrata Storti Foundation
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Original Articles

Study of the effects of proteasome inhibitors on ribosomal protein S19 (RPS19) mutants, identified in patients with Diamond-Blackfan anemia

Aurore Crétien1,2, Corinne Hurtaud1,2, Hélène Moniz1,2, Alexis Proust3, Isabelle Marie3,4, Orianne Wagner-Ballon1,2,5, Valérie Choesmel6,7, Pierre-Emmanuel Gleizes6,7, Thierry Leblanc4,8, Jean Delaunay3,4, Gil Tchernia4, Narla Mohandas9, Lydie Da Costa1,4,10

1 INSERM U790, Villejuif, France
2 Univ Paris-Sud, Villejuif, France
3 AP-HP, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France
4 Centre de référence des maladies génétiques de l’érythrocyte et de l’érythropoïèse, Hôpital Bicêtre, Université Paris XI, Le Kremlin-Bicêtre, France
5 AP-HP, Hôpital Henri-Mondor, Créteil, France
6 Université Paul Sabatier, Laboratoire de Biologie Moléculaire des Eucaryotes, Toulouse, France
7 CNRS, UMR5099, Toulouse, France
8 AP-HP, Hôpital Saint-Louis, Paris, France
9 New York Blood Center, New York, NY, USA and
10 AP-HP, Hôpital Robert-Debré, Paris, France

Correspondence: Lydie Da Costa, MD, PHD, Service, d’Hématologie biologique, Hôpital, Robert Debré, 48 boulevard Sérurier, 75019 Paris, France. E-mail:lydiedacosta{at}free.fr/lydie.dacosta{at}rdb.aphp.fr

Background: Mutations in the ribosomal protein S19 gene (RPS19) have been found in 25% of patients with Diamond-Blackfan anemia, a rare syndrome of congenital bone marrow failure characterized by erythroblastopenia and various malformations. Mechanistic understanding of the role of RPS19 in normal erythropoiesis and in the Diamond-Blackfan anemia defect is still poor. However, defective ribosome biogenesis and, in particular, impaired 18S ribosomal RNA maturation have been documented in association with various identified RPS19 mutations. Recently, new genes, all encoding ribosomal proteins, have been found to be mutated in Diamond-Blackfan anemia, adding further support to the concept that ribosome biogenesis plays an important role in regulating erythropoiesis. We previously showed variability in the levels of expression and subcellular localization of a subset of RPS19 mutant proteins.

Design and Methods: To define the mechanistic basis for this variability better, we studied a large number of mutant proteins and characterized both RPS19 expression level using a specific antibody against RPS19 and RPS19 subcellular localization after transfection of Cos-7 cells with various green fluorescent protein-RPS19 mutants. To investigate the role of the proteasome in RPS19 degradation, we examined the effect of various proteasome inhibitors, namely lactacystin, MG132, and bortezomib on RPS19 expression and subcellular localization

Results: We found two distinct classes of RPS19 protein defects in Diamond-Blackfan anemia based on the stability of the mutant proteins: (i) slightly decreased to normal levels of expression and normal nucleolar localization and (ii) markedly deficient expression and failure to localize to the nucleolus. All the proteasome inhibitors tested were able to restore the expression levels and normal subcellular localization of several unstable mutant proteins.

Conclusions: Our findings demonstrate an important role for the proteasomal degradation pathway in regulating the expression levels and nucleolar localization of certain mutant RPS19 proteins in Diamond-Blackfan anemia.

Key words: RPS19, Diamond-Blackfan anemia, nucleolar localization, proteasome inhibitors, bortezomib.


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Diamond-Blackfan anemia: a ribosomal puzzle
Irma Dianzani, Fabrizio Loreni
Haematologica 2008 93: 1601-1604. [Full Text] [PDF]



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I. Dianzani and F. Loreni
Diamond-Blackfan anemia: a ribosomal puzzle
Haematologica, November 1, 2008; 93(11): 1601 - 1604.
[Full Text] [PDF]