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SiRNA knockdown of ribosomal protein gene RPL19 abrogates the aggressive phenotype of human prostate cancer

ABSTRACT: Ribosomal protein RPL19 is an integral component of eukaryotic ribosomes and universally involved in protein synthesis. Although consistently stable in normal cells, RPL19 transcription is relatively elevated in prostate cancer. Using siRNA, we inhibited RPL19 transcription and demonstrated the gene to be functionally involved in promoting the malignant phenotype. Reducing RPL19 modulates a subset of genes rather than globally down-regulating protein synthesis, as evidenced by Western blotting and maintenance of cell proliferation. Mechanistically, either all ribosomes are not structurally and functionally identical or absence of RPL19 is compensated by other ribosomal protein genes. Following RPL19 inhibition, gene expression analysis confirms induction of the non-malignant phenotype principally to involve perturbation of transcription factor networks and cellular adhesion genes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE26774 | GEO | 2011/12/08

SECONDARY ACCESSION(S): PRJNA136283

REPOSITORIES: GEO

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siRNA knockdown of ribosomal protein gene RPL19 abrogates the aggressive phenotype of human prostate cancer

Project description:Ribosomal protein RPL19 is an integral component of eukaryotic ribosomes and universally involved in protein synthesis. Although consistently stableM-BM- in normal cells, RPL19 transcription is relatively elevated in prostate cancer. Using siRNA, we inhibited RPL19 transcription and demonstrated the gene to be functionally involved in promoting the malignant phenotype. Reducing RPL19 modulates a subset of genes rather than globally down-regulating protein synthesis, as evidenced by Western blotting and maintenance of cell proliferation. Mechanistically, either all ribosomes are not structurally and functionally identical or absence of RPL19 is compensated by other ribosomal protein genes. Following RPL19 inhibition, gene expression analysis confirms induction of the non-malignant phenotype principally to involve perturbation of transcription factor networks and cellular adhesion genes. 10 microarray experiments were analysed using five different prostate cell types: PC3M, PNT2, PC3M with stable knockdown transfection, PC3M with a scrambled virus and various PC3M knockdowns pooled

2011-12-08 | E-GEOD-26774 | biostudies-arrayexpress

Tau drives translational selectivity by interacting with ribosomal proteins

Project description:There is a fundamental gap in understanding the consequences of tau-ribosome interactions. Tau oligomers and filaments hinder protein synthesis in vitro, and they associate strongly with ribosomes in vivo. Here, we investigated the consequences of tau interactions with ribosomes in vivo and in human brain tissues to identify tau as a direct modulator of ribosomal selectivity. We performed microarrays and nascent proteomics to measure changes in protein synthesis using rTg4510 tau transgenic mice. We determined that tau expression differentially shifts the transcriptome and the proteome and that the synthesis of ribosomal proteins is reversibly dependent on tau levels. We further extended these results to human brains and show that tau pathologically interacts with ribosomal protein S6 (rpS6 or S6). Consequently, synthesis of ribosomal proteins coded by 5’TOP-mRNAs was reduced under tauopathic conditions in Alzheimer’s disease brains. Our data establish tau as a driver of RNA translation selectivity. Moreover, considering that regulation of protein synthesis is critical to learning and memory, aberrant tau-ribosome interactions in disease could explain the linkage between virtually every tauopathy and cognitive impairment and memory decline.

2019-03-30 | GSE121264 | GEO

Sch9 regulates ribosome biogenesis via Stb3, Dot6 and Tod6 and the histone deacetylase complex RPD3L (mRNA-Seq data)

Project description:TORC1 is a structurally and functionally conserved multiprotein complex that regulates many aspects of eukaryote growth including the synthesis and assembly of ribosomes. The protein kinase activity of this complex is responsive to environmental cues and is potently inhibited by the natural product macrolide rapamycin. Insights into how TORC1 regulates growth have been provided with the recent identification of the rapamycin-sensitive phosphoproteome in yeast. Building on these data, we show here that Sch9, an AGC family kinase and direct substrate of TORC1, promotes ribosome biogenesis (ribi) and ribosomal protein (RP) gene expression via direct inhibitory phosphorylation of three transcription repressors, Stb3, Dot6 and Tod6. Dephosphorylation of these factors allows them to recruit the RPD3L histone deactelyase complex to ribi/RP gene promoters. Since rRNA and tRNA transcription are also under its control, Sch9 appears to be well positioned to coordinately regulate transcriptional aspects of ribosome biogenesis. mRNA-Seq of 8 S. cerevisiae strains treated with either DMSO alone or 1NM-PP1, a small molecule inhibitor for analog-sensitive kinases such as sch9-as.

2011-07-01 | E-GEOD-29122 | biostudies-arrayexpress

Sch9 regulates ribosome biogenesis via Stb3, Dot6 and Tod6 and the histone deacetylase complex RPD3L (ChIP-Seq data)

Project description:TORC1 is a structurally and functionally conserved multiprotein complex that regulates many aspects of eukaryote growth including the synthesis and assembly of ribosomes. The protein kinase activity of this complex is responsive to environmental cues and is potently inhibited by the natural product macrolide rapamycin. Insights into how TORC1 regulates growth have been provided with the recent identification of the rapamycin-sensitive phosphoproteome in yeast. Building on these data, we show here that Sch9, an AGC family kinase and direct substrate of TORC1, promotes ribosome biogenesis (ribi) and ribosomal protein (RP) gene expression via direct inhibitory phosphorylation of three transcription repressors, Stb3, Dot6 and Tod6. Dephosphorylation of these factors allows them to recruit the RPD3L histone deactelyase complex to ribi/RP gene promoters. Since rRNA and tRNA transcription are also under its control, Sch9 appears to be well positioned to coordinately regulate transcriptional aspects of ribosome biogenesis. ChIP-Seq of 8 S. cerevisiae strains treated with 1NM-PP1, a small molecule inhibitor for analog-sensitive kinases such as sch9-as.

2011-07-01 | E-GEOD-29124 | biostudies-arrayexpress

Cellular economy in fission yeast cells continuously cultured at limited nitrogen resources

Project description:In ribosome biogenesis, a large fraction of ribosomes is used for producing ribosomal proteins. Here, we deal with the question what fraction of ribosomes should be allocated for synthesis of ribosomal proteins to optimize the cellular economy for growth. We define the "r-fraction" as the fraction of mRNA of the ribosomal protein genes out of the total mRNA and simulated how the amount of the total protein is affected by the r-fraction. Then, we empirically measured the amount of protein and RNA in fission yeast cells cultured at a high or low nitrogen source. In the cells cultured at a low nitrogen source, the r-fraction decreased from 0.46 to 0.42 with a 40% reduction of rRNA, but the reduction of the total protein was smaller at 30%. These results indicate that the r-fraction is internally controlled to optimize the efficiency of protein synthesis at a limited cellular cost.

2015-10-22 | GSE68173 | GEO

Sch9 regulates ribosome biogenesis via Stb3, Dot6 and Tod6 and the histone deacetylase complex RPD3L (ChIP-Seq data)

2011-07-01 | GSE29124 | GEO

Sch9 regulates ribosome biogenesis via Stb3, Dot6 and Tod6 and the histone deacetylase complex RPD3L (mRNA-Seq data)

2011-07-01 | GSE29122 | GEO

Translation elongation factor 2 depletion by siRNA in mouse liver leads to mTOR-independent translational upregulation of ribosomal protein genes

Project description:Due to breakthroughs in RNAi and genome editing methods in the past decade, it is now easier than ever to study fine details of protein synthesis in animal models. However, most of our understanding of translation comes from unicellular organisms and cultured mammalian cells. In this study, we demonstrate the feasibility of perturbing protein synthesis in a mouse liver by targeting translation elongation factor 2 (eEF2) with RNAi. We were able to achieve over 90% knockdown efficacy and maintain it for 2 weeks effectively slowing down the rate of translation elongation. As the total protein yield declined, both proteomics and ribosome profiling assays showed robust translational upregulation of ribosomal proteins relative to other proteins. Although all these genes bear the TOP regulatory motif, the branch of the mTOR pathway responsible for translation regulation was not activated. Paradoxically, coordinated translational upregulation of ribosomal proteins only occurred in the liver but not in murine cell culture. Thus, the upregulation of ribosomal transcripts likely occurred via passive mTOR-independent mechanisms. Impaired elongation sequesters ribosomes on mRNA and creates a shortage of free ribosomes. This leads to preferential translation of transcripts with high initiation rates such as ribosomal proteins. Furthermore, severe eEF2 shortage reduces the negative impact of positively charged amino acids frequent in ribosomal proteins on ribosome progression.

2020-05-31 | GSE136091 | GEO

Mutant huntingtin stalls ribosomes and represses protein synthesis in a cellular model of Huntington disease (mRNA-Seq)

Project description:The polyglutamine expansion of huntingtin (mHtt) causes Huntington disease (HD) and neurodegeneration, but the mechanisms remain unclear. Here, we found that mHtt promotes ribosome stalling and suppresses protein synthesis. Depletion of mHtt enhances protein synthesis and increases the speed of ribosome translocation, while mHtt directly inhibits protein synthesis in vitro. We found interactions of ribosomal proteins and translating ribosomes with mHtt. High-resolution global ribosome footprint profiling (Ribo-Seq) and mRNA-Seq indicated a widespread shift in ribosome occupancy toward the 5’ and 3’ end and unique single-codon pauses on selected mRNA targets in HD cells, compared to controls. Thus, mHtt impedes ribosomal translocation during translation by promoting ribosome stalling, a novel mechanistic defect that can be exploited for HD therapeutics.

2021-02-13 | GSE166695 | GEO

Mutant huntingtin stalls ribosomes and represses protein synthesis in a cellular model of Huntington disease [Ribo-seq]

2020-07-22 | GSE146674 | GEO

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