The rise of a ribosomopathy and increased cancer risk

Luft, Friedrich C.

doi:10.1007/s00109-009-0570-0

Cited by 23 publications

(19 citation statements)

References 9 publications

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“…The term 'ribosomopathy' has been coined to describe clinical manifestations of ribosome biogenesis stress disorders (Luft, 2010). One of the most frequent and well-characterized ribosome biogenesis diseases is Diamond-Blackfan anemia, a group of inherited bone marrow failure disorders (Ellis et al, 2008).…”

Section: Nucleolar Stress and Human Diseasementioning

confidence: 99%

Ribosome biogenesis surveillance: probing the ribosomal protein-Mdm2-p53 pathway

2010

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Section: Nucleolar Stress and Human Diseasementioning

confidence: 99%

Ribosome biogenesis surveillance: probing the ribosomal protein-Mdm2-p53 pathway

2010

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“…These questions emerged from the analysis of a group of genetic diseases named ribosomopathies that share, as a causative factor, alteration of either a structural component of the ribosome or a protein involved in ribosome biogenesis. 127 The study of these diseases, listed in Table 1, revealed the intriguing and unexpected finding that alteration in a biogenesis factor or a structural component of the ribosome (defined as ribosomal stress) can cause a tissue-specific defect. 4 There is a clear prevalence of hematopoietic cell defects, but other specific alterations are also present (for example, pancreatic insufficiency in X-linked dyskeratosis congenital (DC)).…”

Section: Ribosomes and Cancermentioning

confidence: 99%

Translation factors and ribosomal proteins control tumor onset and progression: how?

2013

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Gene expression is shaped by translational control. The modalities and the extent by which translation factors modify gene expression have revealed therapeutic scenarios. For instance, eukaryotic initiation factor (eIF)4E activity is controlled by the signaling cascade of growth factors, and drives tumorigenesis by favoring the translation of specific mRNAs. Highly specific drugs target the activity of eIF4E. Indeed, the antitumor action of mTOR complex 1 (mTORc1) blockers like rapamycin relies on their capability to inhibit eIF4E assembly into functional eIF4F complexes. eIF4E biology, from its inception to recent pharmacological targeting, is proof-of-principle that translational control is druggable. The case for eIF4E is not isolated. The translational machinery is involved in the biology of cancer through many other mechanisms. First, untranslated sequences on mRNAs as well as noncoding RNAs regulate the translational efficiency of mRNAs that are central for tumor progression. Second, other initiation factors like eIF6 show a tumorigenic potential by acting downstream of oncogenic pathways. Third, genetic alterations in components of the translational apparatus underlie an entire class of inherited syndromes known as 'ribosomopathies' that are associated with increased cancer risk. Taken together, data suggest that in spite of their evolutionary conservation and ubiquitous nature, variations in the activity and levels of ribosomal proteins and translation factors generate highly specific effects. Beside, as the structures and biochemical activities of several noncoding RNAs and initiation factors are known, these factors may be amenable to rational pharmacological targeting. The future is to design highly specific drugs targeting the translational apparatus.

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“…In addition to the 80 known ribosomal proteins (RPs), Sbds is one of ~150 non-ribosomal proteins required to assemble a functional 80S ribosome (Deisenroth and Zhang, 2010). In addition to SDS, other diseases with causal mutations in genes related to ribosome assembly have been described and are collectively referred to as ribosomopathies (Luft, 2010;Narla and Ebert, 2010). One well-characterized ribosomopathy, Diamond-Blackfan anemia (DBA), is commonly associated with mutations in the RP gene RPS19 (Draptchinskaia et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Ribosomal biogenesis genes play an essential and p53-independent role in zebrafish pancreas development

et al. 2012

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SUMMARYMutations in the human Shwachman-Bodian-Diamond syndrome (SBDS) gene cause defective ribosome assembly and are associated with exocrine pancreatic insufficiency, chronic neutropenia and skeletal defects. However, the mechanism underlying these phenotypes remains unclear. Here we show that knockdown of the zebrafish sbds ortholog fully recapitulates the spectrum of developmental abnormalities observed in the human syndrome, and further implicate impaired proliferation of ptf1a-expressing pancreatic progenitor cells as the basis for the observed pancreatic phenotype. It is thought that diseases of ribosome assembly share a p53-dependent mechanism. However, loss of p53 did not rescue the developmental defects associated with loss of zebrafish sbds. To clarify the molecular mechanisms underlying the observed organogenesis defects, we performed transcriptional profiling to identify candidate downstream mediators of the sbds phenotype. Among transcripts displaying differential expression, functional group analysis revealed marked enrichment of genes related to ribosome biogenesis, rRNA processing and translational initiation. Among these, ribosomal protein L3 (rpl3) and pescadillo (pes) were selected for additional analysis. Similar to knockdown of sbds, knockdown or mutation of either rpl3 or pes resulted in impaired expansion of pancreatic progenitor cells. The pancreatic phenotypes observed in rpl3-and pes-deficient embryos were also independent of p53. Together, these data suggest novel p53-independent roles for ribosomal biogenesis genes in zebrafish pancreas development.

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The rise of a ribosomopathy and increased cancer risk

Cited by 23 publications

References 9 publications

Ribosome biogenesis surveillance: probing the ribosomal protein-Mdm2-p53 pathway

Ribosome biogenesis surveillance: probing the ribosomal protein-Mdm2-p53 pathway

Translation factors and ribosomal proteins control tumor onset and progression: how?

Ribosomal biogenesis genes play an essential and p53-independent role in zebrafish pancreas development

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