Combinatorial action of transcription factors orchestrates cell cycle-dependent expression of the ribosomal protein genes and ribosome biogenesis

FEBS Journal ◽  
2014 ◽  
Vol 281 (10) ◽  
pp. 2339-2352 ◽  
Author(s):  
Nagisa Nosrati ◽  
Neetu R. Kapoor ◽  
Vijay Kumar
Keyword(s):  
Cell Cycle ◽  
Transcription Factors ◽  
Ribosomal Protein ◽  
Ribosome Biogenesis ◽  
Ribosomal Protein Genes ◽  
Cycle Dependent

scholarly journals Ribosomal Protein S6 Gene Haploinsufficiency Is Associated with Activation of a p53-Dependent Checkpoint during Gastrulation

2006 ◽  
Vol 26 (23) ◽  
pp. 8880-8891 ◽  
Author(s):  
Linda Panić ◽  
Sanda Tamarut ◽  
Melanie Sticker-Jantscheff ◽  
Martina Barkić ◽  
Davor Solter ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Embryonic Development ◽  
Ribosomal Protein ◽  
Ribosome Biogenesis ◽  
Fetal Liver ◽  
Genetic Inactivation ◽  
Developmental Program ◽  
Ribosomal Protein S6 ◽  
M Phase ◽  
Insight Into

ABSTRACT Nascent ribosome biogenesis is required during cell growth. To gain insight into the importance of this process during mouse oogenesis and embryonic development, we deleted one allele of the ribosomal protein S6 gene in growing oocytes and generated S6-heterozygous embryos. Oogenesis and embryonic development until embryonic day 5.5 (E5.5) were normal. However, inhibition of entry into M phase of the cell cycle and apoptosis became evident post-E5.5 and led to perigastrulation lethality. Genetic inactivation of p53 bypassed this checkpoint and prolonged development until E12.5, when the embryos died, showing decreased expression of D-type cyclins, diminished fetal liver erythropoiesis, and placental defects. Thus, a p53-dependent checkpoint is activated during gastrulation in response to ribosome insufficiency to prevent improper execution of the developmental program.

scholarly journals RRS1, a Conserved Essential Gene, Encodes a Novel Regulatory Protein Required for Ribosome Biogenesis inSaccharomyces cerevisiae

2000 ◽  
Vol 20 (6) ◽  
pp. 2066-2074 ◽  
Author(s):  
Akiko Tsuno ◽  
Keita Miyoshi ◽  
Rota Tsujii ◽  
Tokichi Miyakawa ◽  
Keiko Mizuta
Keyword(s):  
Ribosomal Protein ◽  
Signaling Pathway ◽  
Transcriptional Repression ◽  
Ribosome Biogenesis ◽  
Essential Gene ◽  
Regulatory Protein ◽  
Rrna Genes ◽  
Amino Acid Residues ◽  
Ribosomal Protein Genes ◽  
Gene Encoding

ABSTRACT A secretory defect causes specific and significant transcriptional repression of both ribosomal protein and rRNA genes (K. Mizuta and J. R. Warner, Mol. Cell. Biol. 14:2493–2502, 1994), suggesting the coupling of plasma membrane and ribosome syntheses. In order to elucidate the molecular mechanism of the signaling pathway, we isolated a cold-sensitive mutant with a mutation in a gene termedRRS1 (regulator of ribosome synthesis), which appeared to be defective in the signaling pathway. The rrs1-1 mutation greatly reduced transcriptional repression of both rRNA and ribosomal protein genes that is caused by a secretory defect. RRS1 is a novel, essential gene encoding a nuclear protein of 203 amino acid residues that is conserved in eukaryotes. A conditionalrrs1-null mutant was constructed by placingRRS1 under the control of the GAL1 promoter. Rrs1p depletion caused defects in processing of pre-rRNA and assembly of ribosomal subunits.

scholarly journals Parallel Concerted Evolution of Ribosomal Protein Genes in Fungi and Its Adaptive Significance

2019 ◽  
Vol 37 (2) ◽  
pp. 455-468 ◽  
Author(s):  
Alison Mullis ◽  
Zhaolian Lu ◽  
Yu Zhan ◽  
Tzi-Yuan Wang ◽  
Judith Rodriguez ◽  
...  
Keyword(s):  
Ribosomal Protein ◽  
Concerted Evolution ◽  
Ribosome Biogenesis ◽  
Gene Dosage ◽  
High Growth ◽  
Transcript Abundance ◽  
Fungal Species ◽  
Physiological Data ◽  
Ribosomal Protein Genes ◽  
Duplication Events

Abstract Ribosomal protein (RP) genes encode structural components of ribosomes, the cellular machinery for protein synthesis. A single functional copy has been maintained in most of 78–80 RP families in animals due to evolutionary constraints imposed by gene dosage balance. Some fungal species have maintained duplicate copies in most RP families. The mechanisms by which the RP genes were duplicated and maintained and their functional significance are poorly understood. To address these questions, we identified all RP genes from 295 fungi and inferred the timing and nature of gene duplication events for all RP families. We found that massive duplications of RP genes have independently occurred by different mechanisms in three distantly related lineages: budding yeasts, fission yeasts, and Mucoromycota. The RP gene duplicates in budding yeasts and Mucoromycota were mainly created by whole genome duplication events. However, duplicate RP genes in fission yeasts were likely generated by retroposition, which is unexpected considering their dosage sensitivity. The sequences of most RP paralogs have been homogenized by repeated gene conversion in each species, demonstrating parallel concerted evolution, which might have facilitated the retention of their duplicates. Transcriptomic data suggest that the duplication and retention of RP genes increased their transcript abundance. Physiological data indicate that increased ribosome biogenesis allowed these organisms to rapidly consume sugars through fermentation while maintaining high growth rates, providing selective advantages to these species in sugar-rich environments.

scholarly journals Cell cycle-dependent transcription factors control the expression of yeast telomerase RNA

RNA ◽  
2013 ◽  
Vol 19 (7) ◽  
pp. 992-1002 ◽  
Author(s):  
I. Dionne ◽  
S. Larose ◽  
A. T. Dandjinou ◽  
S. Abou Elela ◽  
R. J. Wellinger
Keyword(s):  
Cell Cycle ◽  
Transcription Factors ◽  
Telomerase Rna ◽  
Yeast Telomerase ◽  
Cycle Dependent

scholarly journals The RNA Binding Activity of a Ribosome Biogenesis Factor, Nucleophosmin/B23, Is Modulated by Phosphorylation with a Cell Cycle-dependent Kinase and by Association with Its Subtype

2002 ◽  
Vol 13 (6) ◽  
pp. 2016-2030 ◽  
Author(s):  
Mitsuru Okuwaki ◽  
Masafumi Tsujimoto ◽  
Kyosuke Nagata
Keyword(s):  
Cell Cycle ◽  
Ribosome Biogenesis ◽  
Cellular Localization ◽  
Rna Binding ◽  
Intracellular Localization ◽  
Binding Activity ◽  
Cyclin B ◽  
Cycle Dependent

Nucleophosmin/B23 is a nucleolar phosphoprotein. It has been shown that B23 binds to nucleic acids, digests RNA, and is localized in nucleolar granular components from which preribosomal particles are transported to cytoplasm. The intracellular localization of B23 is significantly changed during the cell cycle. Here, we have examined the cellular localization of B23 proteins and the effect of mitotic phosphorylation of B23.1 on its RNA binding activity. Two splicing variants of B23 proteins, termed B23.1 and B23.2, were complexed both in vivo and in vitro. The RNA binding activity of B23.1 was impaired by hetero-oligomer formation with B23.2. Both subtypes of B23 proteins were phosphorylated during mitosis by cyclin B/cdc2. The RNA binding activity of B23.1 was repressed through cyclin B/cdc2-mediated phosphorylation at specific sites in B23. Thus, the RNA binding activity of B23.1 is stringently modulated by its phosphorylation and subtype association. Interphase B23.1 was mainly localized in nucleoli, whereas B23.2 and mitotic B23.1, those of which were incapable of binding to RNA, were dispersed throughout the nucleoplasm and cytoplasm, respectively. These results suggest that nucleolar localization of B23.1 is mediated by its ability to associate with RNA.

scholarly journals Ribosomal and hematopoietic defects in induced pluripotent stem cells derived from Diamond Blackfan anemia patients

Blood ◽  
2013 ◽  
Vol 122 (6) ◽  
pp. 912-921 ◽  
Author(s):  
Loïc Garçon ◽  
Jingping Ge ◽  
Shwetha H. Manjunath ◽  
Jason A. Mills ◽  
Marisa Apicella ◽  
...  
Keyword(s):  
Stem Cells ◽  
Ribosomal Protein ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Ribosome Biogenesis ◽  
Ribosomal Protein Genes ◽  
Diamond Blackfan Anemia ◽  
Key Points ◽  
Induced Pluripotent

Key PointsRibosome biogenesis and hematopoiesis are impaired in iPSCs from DBA patients. The abnormalities of DBA iPSCs are ameliorated by genetic restoration of the defective ribosomal protein genes.

scholarly journals Human Ribosomal Proteins RPeL27, RPeL43, and RPeL41 Are Upregulated in Nasopharyngeal Carcinoma Cell Lines

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Edmund Ui-Hang Sim ◽  
Stella Li-Li Chan ◽  
Kher-Lee Ng ◽  
Choon-Weng Lee ◽  
Kumaran Narayanan
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Ribosomal Protein ◽  
Cell Lines ◽  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Expression Patterns ◽  
Transcript Level ◽  
Ribosomal Protein Genes ◽  
Significant Differential Expression ◽  
Protein Levels

Apart from their canonical role in ribosome biogenesis, there is increasing evidence of ribosomal protein genes’ involvement in various cancers. A previous study by us revealed significant differential expression of three ribosomal protein genes (RPeL27, RPeL41, and RPeL43) between cell lines derived from tumor and normal nasopharyngeal epithelium. However, the results therein were based on a semiquantitative assay, thus preliminary in nature. Herein, we provide findings of a deeper analysis of these three genes in the context to nasopharyngeal carcinoma (NPC) tumorigenesis. Their expression patterns were analyzed in a more quantitative manner at transcript level. Their protein expression levels were also investigated. We showed results that are contrary to previous report. Rather than downregulation, these genes were significantly overexpressed in NPC cell lines compared to normal control at both transcript and protein levels. Nevertheless, their association with NPC has been established. Immunoprecipitation pulldown assays indicate the plausible interaction of either RPeL27 or RPeL43 with POTEE/TUBA1A and ACTB/ACTBL2 complexes. In addition, RPeL43 is shown to bind with MRAS and EIF2S1 proteins in a NPC cell line (HK1). Our findings support RPeL27, RPeL41, and RPeL43 as potential markers of NPC and provide insights into the interaction targets of RPeL27 and RPeL43 proteins.

scholarly journals Eaf1p Is Required for Recruitment of NuA4 in Targeting TFIID to the Promoters of the Ribosomal Protein Genes for Transcriptional InitiationIn Vivo

2015 ◽  
Vol 35 (17) ◽  
pp. 2947-2964 ◽  
Author(s):  
Bhawana Uprety ◽  
Rwik Sen ◽  
Sukesh R. Bhaumik
Keyword(s):  
Ribosomal Protein ◽  
Ribosome Biogenesis ◽  
Protein Gene ◽  
Ribosomal Protein Gene ◽  
Ribosomal Protein Genes ◽  
Transcriptional Initiation ◽  
Independent Form ◽  
Dependent Form ◽  
Histone Acetyltransferase Activity

NuA4 (nucleosome acetyltransferase of H4) promotes transcriptional initiation of TFIID (a complex of TBP and TBP-associated factors [TAFs])-dependent ribosomal protein genes involved in ribosome biogenesis. However, it is not clearly understood how NuA4 regulates the transcription of ribosomal protein genes. Here, we show that NuA4 is recruited to the promoters of ribosomal protein genes, such asRPS5,RPL2B, andRPS11B, for TFIID recruitment to initiate transcription, and the recruitment of NuA4 to these promoters is impaired in the absence of its Eaf1p component. Intriguingly, impaired NuA4 recruitment in aΔeaf1strain depletes recruitment of TFIID (a TAF-dependent form of TBP) but not the TAF-independent form of TBP to the promoters of ribosomal protein genes. However, in the absence of NuA4, SAGA (Spt-Ada-Gcn5-acetyltransferase) is involved in targeting the TAF-independent form of TBP to the promoters of ribosomal protein genes for transcriptional initiation. Thus, NuA4 plays an important role in targeting TFIID to the promoters of ribosomal protein genes for transcriptional initiationin vivo. Such a function is mediated via its targeted histone acetyltransferase activity. In the absence of NuA4, ribosomal protein genes lose TFIID dependency and become SAGA dependent for transcriptional initiation. Collectively, these results provide significant insights into the regulation of ribosomal protein gene expression and, hence, ribosome biogenesis and functions.

Characterization of the Hematologic Phenotype of rpS6 Heterozygous Null Mice as a Model of the Erythroid Failure In Diamond-Blackfan Anemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2033-2033
Author(s):  
Sioban B. Keel ◽  
Janis L. Abkowitz
Keyword(s):  
Ribosomal Protein ◽  
Ribosome Biogenesis ◽  
Conflicts Of Interest ◽  
Macrocytic Anemia ◽  
Ribosomal Subunit ◽  
T Test ◽  
Ribosomal Protein Genes ◽  
Diamond Blackfan Anemia ◽  
Student’S T ◽  
Student’S T Test

Abstract Abstract 2033 Diamond-Blackfan Anemia (DBA) is a congenital form of pure red cell aplasia characterized by a hypoproliferative, macrocytic anemia, congenital anomalies, and a predisposition to cancer. DBA, along with a growing number of human diseases, is linked to defects in ribosome biogenesis. Mutations in at least 10 ribosomal protein genes of both the 40S and 60S ribosomal subunits have now been identified in over 50% of patients with DBA (Narla A, et al. Blood 2010; 115) resulting in ribosomal protein haploinsufficency and in turn a defect in ribosome biogenesis. It remains, however, unknown how these events culminate in erythroid marrow failure. The study of this pathophysiology has been hindered by a lack of animal models. We became aware of the Rps6-deleted mouse as a potential murine model of DBA (Volarevic S, et al. Science 2000; 288). RPS6 is another 40S ribosomal subunit protein required for ribosomal subunit assembly. Haploinsufficiency of RPS6 causes a phenotype reminiscent of DBA during embryogenesis (Panic L, et al. Mol Cell Biol 2006; 26), however, the erythropoietic phenotype of the conditionally-deleted Rps6 heterozygous mouse was unknown. The purpose of these studies is to fully characterize the erythroid phenotype of this mouse as a model of DBA. We demonstrate that deletion of one Rps6 allele in mice results in a macrocytic anemia and leukopenia (an absolute neutropenia and lymphocytopenia, Table 1). Though this finding is not typical, neutropenia has been described in DBA. Like DBA, the anemia is hypoproliferative (corrected reticulocyte counts were equivalent in rpS6 heterozygous and control mice: 3.3% ± 0.21, n= 3 vs. 3.6 ± 0.33, n=3; two-tailed Student's t-test, p= 0.08, which is an inappropriately low value given the deleted animals’ anemia). Flow cytometric analyses of bone marrow and spleen double-stained for Ter119 and transferrin receptor (CD71) demonstrate impaired early erythroid differentiation, evidenced by a relative expansion in the proerythroblast and basophilic erythroblast populations. Hematopoietic colony assays confirm this early defect. These data suggest that haploinsufficiency of rpS6 impacts both erythropoiesis and granulopoiesis, and since the mice are not thrombocytopenic, the effect appears lineage specific, rather than occurring in a common progenitor cell. Polysome profiles to confirm a defect in ribosome biogenesis are pending. Since heterozygous mice recapitulate the erythroid phenotype of DBA, we treated the mice with standard and potential DBA therapies. Specifically, mice received 2 mg/kg/day of prednisone for 12 weeks. There was no improvement in the hemoglobin or MCV in treated animals. As DBA and 5q- syndrome myelodysplastic syndrome (MDS) share an erythroid phenotype and both result from a haploinsufficiency of a ribosomal protein, we also tested whether the macrocytic anemia in rpS6 heterozygous mice responds to lenalidomide (Revlimid®, gift from Celgene Corporation, San Diego, CA). Mice received 3 mg/kg/day of lenalidomide by oral gavage for 12 weeks. The hemoglobin increased in control mice and markedly increased in rpS6 heterozygous mice after 12 weeks of therapy (13.5 ± 0.4 to 14.9 ± 0.2, p= 0.0 and 7.9 g/dL ± 0.9 to 10.3 ± 0.8, p= 0.01, respectively; mean ± SEM, Student's t-test, paired). Additionally, the MCV decreased with therapy in both groups (49.1 fL ± 1.4 to 41.1 ± 0.2, p=0.005 and 57.4 ± 1.1 to 53.77 ± 1.4, p=0.08). With the caveat that we did not monitor drug levels achieved in vivo, these data suggest that lenalidomide improves hemoglobinization and deserves further study in DBA. Disclosures: No relevant conflicts of interest to declare.

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