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

Autor: Irma Dianzani, Rossella Crescitelli, Antonella Ronchi, Elisa Robotti, Stefano Gustincich, Lydie Da Costa, Elisa Pavesi, Emilio Marengo, Hélène Moniz, Paola Roncaglia, Anna Aspesi, Claudio Santoro, Narla Mohandas, Steven R. Ellis, Simone Merlin, Ugo Ramenghi, Ilenia Boria, Antonia Follenzi, Federica Avondo
Přispěvatelé: Aspesi, A, Pavesi, E, Robotti, E, Crescitelli, R, Boria, I, Avondo, F, Moniz, H, Da Costa, L, Mohandas, N, Roncaglia, P, Ramenghi, U, Ronchi, A, Gustincich, S, Merlin, S, Marengo, E, Ellis, S, Follenzi, A, Santoro, C, Dianzani, I
Jazyk: angličtina
Rok vydání: 2014
Předmět:
Ribosomal Proteins
Ribosomal protein
Diamond Blackfan Anemia
Ribosomopathy
Bone marrow failure
Transcription
Genetic
Short Communication
DNA Mutational Analysis
BIO/18 - GENETICA
Biology
Ribosome
RP
ribosomal protein
Cell Line
03 medical and health sciences
0302 clinical medicine
Settore BIO/13 - Biologia Applicata
Gene Order
medicine
Genetics
Humans
Diamond–Blackfan anemia
030304 developmental biology
DBA
Diamond Blackfan anemia
GO
gene ontology
Anemia
Diamond-Blackfan
Regulation of gene expression
0303 health sciences
PCA
principal component analysis
Reproducibility of Results
Molecular Sequence Annotation
General Medicine
PC
principal component
Ribosomal RNA
Cell redox homeostasis
medicine.disease
Cellular amino acid metabolic process
Alternative Splicing
Phenotype
Gene Expression Regulation
030220 oncology & carcinogenesis
RS
ribosomal stress
Mutation
Tumor Suppressor Protein p53
Transcriptome
Zdroj: Gene
ISSN: 0378-1119
DOI: 10.1016/j.gene.2014.04.077
Popis: 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.
Highlights • Ribosomopathies such as DBA are caused by ribosome dysfunction that activates p53. • p53-independent pathways may suggest possible treatments for DBA. • Expression analysis was performed in three p53-null models of DBA. • Genes involved in apoptosis and cell redox homeostasis were especially affected. • DBA is due to cumulative effects of p53-dependent and independent pathways.
Databáze: OpenAIRE
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