Ribosomal Proteins Are Overexpressed in Hyperdiploid Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2495-2495
Author(s):  
Niels Weinhold ◽  
John DeVos ◽  
Dirk Hose ◽  
Jean-Francois Rossi ◽  
Benner Axel ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Ribosomal Protein ◽  
Ribosomal Proteins ◽  
Cross Validation ◽  
Gene Dosage ◽  
Misclassification Rate ◽  
Ribosomal Protein Genes ◽  
Training Set ◽  
Global Test

Abstract Multiple myeloma (MM) is proposed to consist of two main pathogenetic groups. While hyperdiploidy (HD) is characterized by multiple trisomies of odd-numbered chromosomes (i.e. 3, 5, 9, 11, 15, and 19), non-hyperdiploid MM (NHD) show frequently one of the several recurrent IgH-translocations. The aim was to compare HD versus NHD by gene expression profiling (GEP). CD138-positive multiple myeloma cells from 74 newly diagnosed MM patients (42 GEP training group (TG), 32 GEP validation group (VG)) were purified by autoMACS-sorting. Sorted cells were analyzed by interphase-FISH with probes specific for 6q21, 8p21, 9q34, 11q23, 13q14, 15q22, 17p13, 19q13 and translocations t(4;14) and t(11;14). HD and NHD were defined by using a copy number score (CS), which was calculated by subtracting the number of probes indicating losses from the number of probes detecting additional copies (CS >0: HD; CS ≤0: NHD). GEP was performed with Affymetrix DNA-microarrays. Nearest shrunken centroid classification (NSCC) was used to discriminate the different groups, using GCRMA-normalized gene expression values. The prediction error was estimated by means of nested cross-validation using 10 repetitions of 10-fold cross-validation within the training set and separately calculated by use of the NSCC classifier of the training set to predict the validation set. Goeman’s global test was used to check the influence of ribosomal protein expression between HD and NHD. In the TG, both HD and NHD were found in 21 patients. The VG comprised 13 patients with NHD and 19 patients with HD. NSCC resulted in a predictor for HD versus NHD of 81 probe sets with a cross-validated misclassification rate of 14.2% for the TG and 26.5% for the VG. Three of the top ten genes were ribosomal proteins, overexpressed in patients with HD. Goeman’s global test further showed that ribosomal proteins are overexpressed in HD (TG: p<0.001; VG: p=0.03). Interestingly, ribosomal protein genes located on even-numbered chromosomes were also overexpressed. In conclusion, overexpression of ribosomal proteins independent of their location on odd- or even-numbered chromosomes indicates more than just a gene dosage effect and therefore a pathogenetic role of the upregulation of the ribosomal machinery in HD.

scholarly journals Autoregulation of yeast ribosomal proteins discovered by efficient search for feedback regulation

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Basab Roy ◽  
David Granas ◽  
Fredrick Bragg ◽  
Jonathan A. Y. Cher ◽  
Michael A. White ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ribosomal Protein ◽  
Binding Sites ◽  
Ribosomal Proteins ◽  
Feedback Regulation ◽  
Ribosomal Protein Genes ◽  
Efficient Search ◽  
Fold Reduction

AbstractPost-transcriptional autoregulation of gene expression is common in bacteria but many fewer examples are known in eukaryotes. We used the yeast collection of genes fused to GFP as a rapid screen for examples of feedback regulation in ribosomal proteins by overexpressing a non-regulatable version of a gene and observing the effects on the expression of the GFP-fused version. We tested 95 ribosomal protein genes and found a wide continuum of effects, with 30% showing at least a 3-fold reduction in expression. Two genes, RPS22B and RPL1B, showed over a 10-fold repression. In both cases the cis-regulatory segment resides in the 5’ UTR of the gene as shown by placing that segment of the mRNA upstream of GFP alone and demonstrating it is sufficient to cause repression of GFP when the protein is over-expressed. Further analyses showed that the intron in the 5’ UTR of RPS22B is required for regulation, presumably because the protein inhibits splicing that is necessary for translation. The 5’ UTR of RPL1B contains a sequence and structure motif that is conserved in the binding sites of Rpl1 orthologs from bacteria to mammals, and mutations within the motif eliminate repression.

scholarly journals Ribosomal proteins: mutant phenotypes by the numbers and associated gene expression changes

Open Biology ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 200114
Author(s):  
Michael Polymenis
Keyword(s):  
Gene Expression ◽  
Ribosomal Protein ◽  
Ribosomal Proteins ◽  
Homo Sapiens ◽  
Ribosome Profiling ◽  
Ribosomal Protein Genes ◽  
Future Studies ◽  
Protein Mutants ◽  
Structural Parts ◽  
Mutant Phenotypes

Ribosomal proteins are highly conserved, many universally so among organisms. All ribosomal proteins are structural parts of the same molecular machine, the ribosome. However, when ribosomal proteins are mutated individually, they often lead to distinct and intriguing phenotypes, including specific human pathologies. This review is an attempt to collect and analyse all the reported phenotypes of each ribosomal protein mutant in several eukaryotes ( Saccharomyces cerevisiae , Caenorhabditis elegans , Drosophila melanogaster , Danio rerio , Mus musculus , Homo sapiens ). These phenotypes were processed with unbiased computational approaches to reveal associations between different phenotypes and the contributions of individual ribosomal protein genes. An overview of gene expression changes in ribosomal protein mutants, with emphasis on ribosome profiling studies, is also presented. The available data point to patterns that may account for most of the observed phenotypes. The information presented here may also inform future studies about the molecular basis of the phenotypes that arise from mutations in ribosomal proteins.

scholarly journals Autoregulation of Many Yeast Ribosomal Proteins Discovered by Efficient Search for Feedback Regulation

2020 ◽  
Author(s):  
Basab Roy ◽  
David Granas ◽  
Fredrick Bragg ◽  
Jonathan A. Y. Cher ◽  
Michael A. White ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ribosomal Protein ◽  
Binding Sites ◽  
Ribosomal Proteins ◽  
Feedback Regulation ◽  
Ribosomal Protein Genes ◽  
Efficient Search ◽  
Bacterial Systems

AbstractPost-transcriptional autoregulation of gene expression is common in bacterial systems but many fewer examples are known in eukaryotes. We used the yeast collection of genes fused to GFP as a rapid screen for examples of feedback regulation in ribosomal proteins by overexpressing a non-regulatable version of a gene and observing the effects on the expression of the GFP-fused version. We tested 95 ribosomal protein genes and found that 21 of them showed at least a three-fold repression. Two genes, RPS22B and RPL1B, showed over a 10-fold repression. In both cases the cis-regulatory segment resides in the 5’ UTR of the gene as shown by placing that segment of the mRNA upstream of GFP alone and demonstrating it is sufficient to cause repression of GFP when the protein is over-expressed. Further analyses showed that the intron in the 5’ UTR of RPS22B is required for regulation, presumably because the protein inhibits splicing that is necessary for translation. The 5’ UTR of RPL1B contains a sequence and structure motif that is conserved in the binding sites of Rpl1 orthologs from bacteria to mammals, and mutations within the motif eliminate repression.

scholarly journals Reduction of Ribosome Level Triggers Flocculation of Fission Yeast Cells

2013 ◽  
Vol 12 (3) ◽  
pp. 450-459 ◽  
Author(s):  
Rongpeng Li ◽  
Xuesong Li ◽  
Lei Sun ◽  
Feifei Chen ◽  
Zhenxing Liu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ribosomal Protein ◽  
Fission Yeast ◽  
Ribosomal Proteins ◽  
Threshold Value ◽  
Yeast Cells ◽  
Ribosomal Protein Genes ◽  
Wild Type ◽  
Transcript Levels ◽  
Biosynthesis Gene

ABSTRACTDeletion of ribosomal protein L32 genes resulted in a nonsexual flocculation of fission yeast. Nonsexual flocculation also occurred when two other ribosomal protein genes,rpl21-2andrpl9-2, were deleted. However, deletion of two nonribosomal protein genes,mpgandfbp, did not cause flocculation. Overall transcript levels ofrpl32inrpl32-1Δ andrpl32-2Δ cells were reduced by 35.9% and 46.9%, respectively, and overall ribosome levels inrpl32-1Δ andrpl32-2Δ cells dropped 31.1% and 27.8%, respectively, compared to wild-type cells. Interestingly, ribosome protein expression levels and ribosome levels were also reduced greatly in sexually flocculating diploid YHL6381/WT (h+/h−) cells compared to a mixture of YHL6381 (h+) and WT (h−) nonflocculating haploid cells. Transcriptome analysis indicated that the reduction of ribosomal levels in sexual flocculating cells was caused by more-extensive suppression of ribosomal biosynthesis gene expression, while the reduction of ribosomal levels caused by deleting ribosomal protein genes in nonsexual flocculating cells was due to an imbalance between ribosomal proteins. We propose that once the reduction of ribosomal levels is below a certain threshold value, flocculation is triggered.

Mild temperature shock alters the transcription of a discrete class of Saccharomyces cerevisiae genes

1983 ◽  
Vol 3 (3) ◽  
pp. 457-465
Author(s):  
C H Kim ◽  
J R Warner
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Ribosomal Protein ◽  
Ribosomal Proteins ◽  
Temperature Shift ◽  
Restrictive Temperature ◽  
Ribosomal Protein Genes ◽  
Wild Type ◽  
Temperature Shock ◽  
Mild Temperature ◽  
Mutant Cells

In Saccharomyces cerevisiae the synthesis of ribosomal proteins declines temporarily after a culture has been subjected to a mild temperature shock, i.e., a shift from 23 to 36 degrees C, each of which support growth. Using cloned genes for several S. cerevisiae ribosomal proteins, we found that the changes in the synthesis of ribosomal proteins parallel the changes in the concentration of mRNA of each. The disappearance and reappearance of the mRNA is due to a brief but severe inhibition of the transcription of each of the ribosomal protein genes, although the total transcription of mRNA in the cells is relatively unaffected by the temperature shock. The precisely coordinated response of these genes, which are scattered throughout the genome, suggests that either they or the enzyme which transcribes them has unique properties. In certain S. cerevisiae mutants, the synthesis of ribosomal proteins never recovers from a temperature shift. Yet both the decline and the resumption of transcription of these genes during the 30 min after the temperature shift are indistinguishable from those in wild-type cells. The failure of the mutant cells to grow at the restrictive temperature appears to be due to their inability to process the RNA transcribed from genes which have introns (Rosbash et al., Cell 24:679-686, 1981), a large proportion of which appear to be ribosomal protein genes.

scholarly journals The yeast omnipotent suppressor SUP46 encodes a ribosomal protein which is a functional and structural homolog of the Escherichia coli S4 ram protein.

Genetics ◽  
1992 ◽  
Vol 132 (2) ◽  
pp. 375-386 ◽  
Author(s):  
A Vincent ◽  
S W Liebman
Keyword(s):  
Escherichia Coli ◽  
Ribosomal Protein ◽  
Dna Sequences ◽  
Ribosomal Proteins ◽  
Amino Acid Sequences ◽  
Ribosomal Protein Genes ◽  
Significant Homology ◽  
A Cell ◽  
Functional Equivalent ◽  
Ribosomal Protein S13

Abstract The accurate synthesis of proteins is crucial to the existence of a cell. In yeast, several genes that affect the fidelity of translation have been identified (e.g., omnipotent suppressors, antisuppressors and allosuppressors). We have found that the dominant omnipotent suppressor SUP46 encodes the yeast ribosomal protein S13. S13 is encoded by two similar genes, but only the sup46 copy of the gene is able to fully complement the recessive phenotypes of SUP46 mutations. Both copies of the S13 genes contain introns. Unlike the introns of other duplicated ribosomal protein genes which are highly diverged, the duplicated S13 genes have two nearly identical DNA sequences of 25 and 31 bp in length within their introns. The SUP46 protein has significant homology to the S4 ribosomal protein in prokaryotic-type ribosomes. S4 is encoded by one of the ram (ribosomal ambiguity) genes in Escherichia coli which are the functional equivalent of omnipotent suppressors in yeast. Thus, SUP46 and S4 demonstrate functional as well as sequence conservation between prokaryotic and eukaryotic ribosomal proteins. SUP46 and S4 are most similar in their central amino acid sequences. Interestingly, the alterations resulting from the SUP46 mutations and the segment of the S4 protein involved in binding to the 16S rRNA are within this most conserved region.

Association of RAP1 binding sites with stringent control of ribosomal protein gene transcription in Saccharomyces cerevisiae

1991 ◽  
Vol 11 (5) ◽  
pp. 2723-2735 ◽  
Author(s):  
C M Moehle ◽  
A G Hinnebusch
Keyword(s):  
Gene Expression ◽  
Saccharomyces Cerevisiae ◽  
Amino Acid ◽  
Ribosomal Protein ◽  
Binding Sites ◽  
Protein Gene ◽  
Ribosomal Protein Gene ◽  
Ribosomal Protein Genes ◽  
Biosynthetic Genes ◽  
Stringent Control

An amino acid limitation in bacteria elicits a global response, called stringent control, that leads to reduced synthesis of rRNA and ribosomal proteins and increased expression of amino acid biosynthetic operons. We have used the antimetabolite 3-amino-1,2,4-triazole to cause histidine limitation as a means to elicit the stringent response in the yeast Saccharomyces cerevisiae. Fusions of the yeast ribosomal protein genes RPL16A, CRY1, RPS16A, and RPL25 with the Escherichia coli lacZ gene were used to show that the expression of these genes is reduced by a factor of 2 to 5 during histidine-limited exponential growth and that this regulation occurs at the level of transcription. Stringent regulation of the four yeast ribosomal protein genes was shown to be associated with a nucleotide sequence, known as the UASrpg (upstream activating sequence for ribosomal protein genes), that binds the transcriptional regulatory protein RAP1. The RAP1 binding sites also appeared to mediate the greater ribosomal protein gene expression observed in cells growing exponentially than in cells in stationary phase. Although expression of the ribosomal protein genes was reduced in response to histidine limitation, the level of RAP1 DNA-binding activity in cell extracts was unaffected. Yeast strains bearing a mutation in any one of the genes GCN1 to GCN4 are defective in derepression of amino acid biosynthetic genes in 10 different pathways under conditions of histidine limitation. These Gcn- mutants showed wild-type regulation of ribosomal protein gene expression, which suggests that separate regulatory pathways exist in S. cerevisiae for the derepression of amino acid biosynthetic genes and the repression of ribosomal protein genes in response to amino acid starvation.

scholarly journals Gene dosage alteration of L2 ribosomal protein genes in Saccharomyces cerevisiae: effects on ribosome synthesis.

1988 ◽  
Vol 8 (11) ◽  
pp. 4792-4798 ◽  
Author(s):  
A Lucioli ◽  
C Presutti ◽  
S Ciafrè ◽  
E Caffarelli ◽  
P Fragapane ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Ribosomal Protein ◽  
Gene Dosage ◽  
Transcriptional Level ◽  
Ribosomal Protein Genes ◽  
Promoter Regions ◽  
Phenotypic Alteration ◽  
Mrna Pool ◽  
Gene Copies ◽  
The Difference

In Saccharomyces cerevisiae, the genes coding for the ribosomal protein L2 are present in two copies per haploid genome. The two copies, which encode proteins differing in only a few amino acids, contribute unequally to the L2 mRNA pool: the L2A copy makes 72% of the mRNA, while the L2B copy makes only 28%. Disruption of the L2B gene (delta B strain) did not lead to any phenotypic alteration, whereas the inactivation of the L2A copy (delta A strain) produced a slow-growth phenotype associated with decreased accumulation of 60S subunits and ribosomes. No intergenic compensation occurred at the transcriptional level in the disrupted strains; in fact, delta A strains contained reduced levels of L2 mRNA, whereas delta B strains had almost normal levels. The wild-type phenotype was restored in the delta A strains by transformation with extra copies of the intact L2A or L2B gene. As already shown for other duplicated genes (Kim and Warner, J. Mol. Biol. 165:79-89, 1983; Leeret al., Curr. Genet. 9:273-277, 1985), the difference in expression of the two gene copies could be accounted for via differential transcription activity. Sequence comparison of the rpL2 promoter regions has shown the presence of canonical HOMOL1 boxes which are slightly different in the two genes.

Multiple Myeloma: Global Expression Profiling (GEP) Indicates Upregulation of the Ribosomal Machinery in Hyperdiploid Clones.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1421-1421
Author(s):  
Friedrich W. Cremer ◽  
John De Vos ◽  
Dirk Hose ◽  
Jean François Rossi ◽  
Carina Ittrich ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Growth ◽  
Ribosomal Protein ◽  
Bone Marrow Cells ◽  
Statistical Investigation ◽  
Classification Error ◽  
Ribosomal Protein Genes ◽  
Validation Group ◽  
Classification Error Rate ◽  
Go Annotation

Abstract Background: In multiple myeloma (MM), deletion of chromosome (chr.) 13q and hypodiploidy are adverse prognostic factors. Prognostic evaluation is frequently based on interphase-fluorescence in-situ hybridization (FISH) with a single probe for chr. 13q14. Patients and methods: CD138-positive bone marrow cells from 97 patients with newly diagnosed MM (58 training group (TG) and 39 validation group (VG)) were enriched by magnetic-activated cell-sorting (median purity, 95%). Sorted cells were analyzed by interphase-FISH with probes for chr. 13q14, and additionally 9q34, 11q23, 19q13, t(11;14), and t(4;14). GEP was performed with Affymetrix U133A+B (TG) and HGU133-2.0plus (VG) microarrays. Nearest shrunken centroids classification (NSC) was applied to discriminate clones with FISH-detected del(13q14) vs. those without, using VSN-normalized gene expression values. Chromosomal localization of predictor genes was determined using the MapIt program, and functional relationship was established by Gene Ontology (GO) annotation and creation of GO-slims. Results: A deletion of chr. 13q14 was found in 27/58 patients (47%) of the training and in 21/39 (54%) of the validation group. Frequencies of trisomies were lower (9q: 48 vs. 74%; 11q: 41 vs. 74%; 19q: 44 vs. 84%) and of IgH translocations higher (48 vs. 16%) in patients with del(13q14). NSC resulted in a predictor for del(13q14) of 378 probe-sets with a cross-validated classification error rate of 22%; the VG is under statistical investigation. Of the predictor genes, 18% were localized on chr. 13 (distributed evenly from 13q12 to 13q33), followed by chr. 19, 11 and 3 (10/6/6%). In the 50 probe-sets with the highest scores, the most frequent localizations of the represented genes were chr. 19, 9, and 13 (12/8/6 of 50). In 8/8 incorrectly classified patients with del(13q14), at least 2 of 3 trisomies (9q, 11q, 19q) were present, hinting at hyperdiploidy. Only 1/5 incorrectly classified patients without del(13q14) harbored 3 trisomies. Biological functions (GO level 3) of predictor genes were related to protein and DNA metabolism (43%), cell growth/maintenance (27%), and cell communication (17%). The most frequent GO term for cellular component was ribosome (34%). Sixty-nine of 80 human ribosomal protein (RP) genes were represented in the predictor, and made up 33 of the top-50 probe-sets. RP genes were overexpressed in patients without del(13q14) compared to plasma cells from 7 normal donors. Expression levels of RPL12, RPLP2 and RPL13A (on chr. 9, 11 and 19) correlated with the respective chr. copy numbers. Conclusion: FISH-detected del(13q14) is associated with non-hyperdiploidy rather than defining an independent subentity of MM. Overexpression of RP-genes in malignancies has been linked to cell growth, disease progression and drug resistance. A possible pathogenetic role of the upregulation of virtually all ribosomal protein genes observed in del(13q)-negative/hyperdiploid MM clones has to be evaluated further.

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