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1
Graifer, Dmitri, and Galina Karpova. "Eukaryotic protein uS19: a component of the decoding site of ribosomes and a player in human diseases." Biochemical Journal 478, no. 5 (March 4, 2021): 997–1008. http://dx.doi.org/10.1042/bcj20200950.
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Proteins belonging to the universal ribosomal protein (rp) uS19 family are constituents of small ribosomal subunits, and their conserved globular parts are involved in the formation of the head of these subunits. The eukaryotic rp uS19 (previously known as S15) comprises a C-terminal extension that has no homology in the bacterial counterparts. This extension is directly implicated in the formation of the ribosomal decoding site and thereby affects translational fidelity in a manner that has no analogy in bacterial ribosomes. Another eukaryote-specific feature of rp uS19 is its essential participance in the 40S subunit maturation due to the interactions with the subunit assembly factors required for the nuclear exit of pre-40S particles. Beyond properties related to the translation machinery, eukaryotic rp uS19 has an extra-ribosomal function concerned with its direct involvement in the regulation of the activity of an important tumor suppressor p53 in the Mdm2/Mdmx-p53 pathway. Mutations in the RPS15 gene encoding rp uS19 are linked to diseases (Diamond Blackfan anemia, chronic lymphocytic leukemia and Parkinson's disease) caused either by defects in the ribosome biogenesis or disturbances in the functioning of ribosomes containing mutant rp uS19, likely due to the changed translational fidelity. Here, we review currently available data on the involvement of rp uS19 in the operation of the translational machinery and in the maturation of 40S subunits, on its extra-ribosomal function, and on relationships between mutations in the RPS15 gene and certain human diseases.
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Grunchec, Héloïse, Jérôme Deraze, Delphine Dardalhon-Cuménal, Valérie Ribeiro, Anne Coléno-Costes, Karine Dias, Sébastien Bloyer, Emmanuèle Mouchel-Vielh, Frédérique Peronnet, and Hélène Thomassin. "Single amino-acid mutation in a Drosoph ila melanogaster ribosomal protein: An insight in uL11 transcriptional activity." PLOS ONE 17, no. 8 (August 18, 2022): e0273198. http://dx.doi.org/10.1371/journal.pone.0273198.
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The ribosomal protein uL11 is located at the basis of the ribosome P-stalk and plays a paramount role in translational efficiency. In addition, no mutant for uL11 is available suggesting that this gene is haplo-insufficient as many other Ribosomal Protein Genes (RPGs). We have previously shown that overexpression of Drosophila melanogaster uL11 enhances the transcription of many RPGs and Ribosomal Biogenesis genes (RiBis) suggesting that uL11 might globally regulate the level of translation through its transcriptional activity. Moreover, uL11 trimethylated on lysine 3 (uL11K3me3) interacts with the chromodomain of the Enhancer of Polycomb and Trithorax Corto, and both proteins co-localize with RNA Polymerase II at many sites on polytene chromosomes. These data have led to the hypothesis that the N-terminal end of uL11, and more particularly the trimethylation of lysine 3, supports the extra-ribosomal activity of uL11 in transcription. To address this question, we mutated the lysine 3 codon using a CRISPR/Cas9 strategy and obtained several lysine 3 mutants. We describe here the first mutants of D. melanogaster uL11. Unexpectedly, the uL11K3A mutant, in which the lysine 3 codon is replaced by an alanine, displays a genuine Minute phenotype known to be characteristic of RPG deletions (longer development, low fertility, high lethality, thin and short bristles) whereas the uL11K3Y mutant, in which the lysine 3 codon is replaced by a tyrosine, is unaffected. In agreement, the rate of translation decreases in uL11K3A but not in uL11K3Y. Co-immunoprecipitation experiments show that the interaction between uL11 and the Corto chromodomain is impaired by both mutations. However, Histone Association Assays indicate that the mutant proteins still bind chromatin. RNA-seq analyses from wing imaginal discs show that Corto represses RPG expression whereas very few genes are deregulated in uL11 mutants. We propose that Corto, by repressing RPG expression, ensures that all ribosomal proteins are present at the correct stoichiometry, and that uL11 fine-tunes its transcriptional regulation of RPGs.
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Pecoraro, Annalisa, Pietro Carotenuto, Brunella Franco, Rossella De Cegli, Giulia Russo, and Annapina Russo. "Role of uL3 in the Crosstalk between Nucleolar Stress and Autophagy in Colon Cancer Cells." International Journal of Molecular Sciences 21, no. 6 (March 20, 2020): 2143. http://dx.doi.org/10.3390/ijms21062143.
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The nucleolus is the site of ribosome biogenesis and has been recently described as important sensor for a variety of cellular stressors. In the last two decades, it has been largely demonstrated that many chemotherapeutics act by inhibiting early or late rRNA processing steps with consequent alteration of ribosome biogenesis and activation of nucleolar stress response. The overall result is cell cycle arrest and/or apoptotic cell death of cancer cells. Our previously data demonstrated that ribosomal protein uL3 is a key sensor of nucleolar stress activated by common chemotherapeutic agents in cancer cells lacking p53. We have also demonstrated that uL3 status is associated to chemoresistance; down-regulation of uL3 makes some chemotherapeutic drugs ineffective. Here, we demonstrate that in colon cancer cells, the uL3 status affects rRNA synthesis and processing with consequent activation of uL3-mediated nucleolar stress pathway. Transcriptome analysis of HCT 116p53−/− cells expressing uL3 and of a cell sub line stably depleted of uL3 treated with Actinomycin D suggests a new extra-ribosomal role of uL3 in the regulation of autophagic process. By using confocal microscopy and Western blotting experiments, we demonstrated that uL3 acts as inhibitory factor of autophagic process; the absence of uL3 is associated to increase of autophagic flux and to chemoresistance. Furthermore, experiments conducted in presence of chloroquine, a known inhibitor of autophagy, indicate a role of uL3 in chloroquine-mediated inhibition of autophagy. On the basis of these results and our previous findings, we hypothesize that the absence of uL3 in cancer cells might inhibit cancer cell response to drug treatment through the activation of cytoprotective autophagy. The restoration of uL3 could enhance the activity of many drugs thanks to its pro-apoptotic and anti-autophagic activity.
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Lucioli, A., C. Presutti, S. Ciafrè, E. Caffarelli, P. Fragapane, and I. Bozzoni. "Gene dosage alteration of L2 ribosomal protein genes in Saccharomyces cerevisiae: effects on ribosome synthesis." Molecular and Cellular Biology 8, no. 11 (November 1988): 4792–98. http://dx.doi.org/10.1128/mcb.8.11.4792-4798.1988.
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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.
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Lucioli, A., C. Presutti, S. Ciafrè, E. Caffarelli, P. Fragapane, and I. Bozzoni. "Gene dosage alteration of L2 ribosomal protein genes in Saccharomyces cerevisiae: effects on ribosome synthesis." Molecular and Cellular Biology 8, no. 11 (November 1988): 4792–98. http://dx.doi.org/10.1128/mcb.8.11.4792.
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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.
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Lee, B. W., E. J. Kwon, Y. Park, J. J. Lee, S. H. Park, and S. K. Kwok. "AB0619 PREDICTORS FOR FUTURE DEVELOPMENT OF SYSTEMIC LUPUS ERYTHEMATOSUS IN KOREAN SJÖGREN’S SYNDROME PATIENTS." Annals of the Rheumatic Diseases 82, Suppl 1 (May 30, 2023): 1511.1–1511. http://dx.doi.org/10.1136/annrheumdis-2023-eular.4636.
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BackgroundSjögren’s syndrome (SS) can occur alone or in combination with other autoimmune diseases. Systemic lupus erythematosus (SLE) is the most common autoimmune disease associated with SS. The prognosis of SS is generally better than that of SLE. However, the onset of SLE in these patients may be one of the factors that increase mortality.ObjectivesThis study determined the impact of demographic factors, clinical manifestations, disease activity, and serological tests at baseline on future SLE development in Sjögren’s syndrome (SS) patients.MethodsThis retrospective study assessed 1,082 SS patients without other autoimmune diseases at baseline who visited our hospital between January 2012 and March 2021. We analyzed demographic features, extra-glandular manifestations (EGMs), clinical indices, and laboratory values at baseline between the two groups divided per future SLE development (SS/SLE group vs. SS group). The probability and predictors of SLE development in SS patients were estimated using the Kaplan–Meier method and Cox proportional hazards models.ResultsThe median follow-up duration was 1083.5 days. Forty-nine patients (4.5%) developed SLE that met the 2012 Systemic Lupus International Collaborating Clinics or 2019 EULAR/ACR classification criteria. The baseline EULAR SS disease activity index (ESSDAI) score was significantly higher in the SS/SLE group (p<0.001). The SS/SLE group had more lymphadenopathy and renal involvement (p=0.015 andp=0.017, respectively). Shorter SS disease duration (<3 years) (hazard ratio [HR]=2.61,p=0.012), high ESSDAI (HR=3.04,p=0.024), leukopenia (HR=2.20,p=0.017), hypocomplementemia (HR=17.40,p<0.0001), and positive for anti-dsDNA (HR=19.93,p<0.0001), anti-ribonucleoprotein (RNP) (HR=2.96,p=0.025), and anti-ribosomal P (HR=2.74,p=0.048) at baseline were SLE development predictors in SS patients.ConclusionShorter disease duration and higher disease activity of SS at baseline may be risk factors for future SLE development. Serologic predictors of SLE development are hypocomplementemia, leukopenia, and positivity for anti-dsDNA, anti-RNP, and anti-ribosomal P antibodies. If the above factors are observed, close monitoring will be necessary during the follow-up period, considering the possibility of future SLE development.References[1]Lazarus MN and Isenberg DA. Development of additional autoimmune diseases in a population of patients with primary Sjogren’s syndrome.Ann Rheum Dis. 2005; 64: 1062-4.[2]Pasoto SG, Adriano de Oliveira Martins V and Bonfa E. Sjogren’s syndrome and systemic lupus erythematosus: links and risks.Open Access Rheumatol. 2019; 11: 33-45Figure 1.Comparison of disease activity (by ESSDAI score) and extraglandular manifestations (EGMs) at baseline between SS/SLE group and SS group.AcknowledgementsNo acknowledgements to declare.Disclosure of InterestsNone Declared.
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Roy, Dipankar Chandra, Sudhangshu Kumar Biswas, Ananda Kumar Saha, Biswanath Sikdar, Mizanur Rahman, Apurba Kumar Roy, Zakaria Hossain Prodhan, and Swee-Seong Tang. "Biodegradation of Crystal Violet dye by bacteria isolated from textile industry effluents." PeerJ 6 (June 21, 2018): e5015. http://dx.doi.org/10.7717/peerj.5015.
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Industrial effluent containing textile dyes is regarded as a major environmental concern in the present world. Crystal Violet is one of the vital textile dyes of the triphenylmethane group; it is widely used in textile industry and known for its mutagenic and mitotic poisoning nature. Bioremediation, especially through bacteria, is becoming an emerging and important sector in effluent treatment. This study aimed to isolate and identify Crystal Violet degrading bacteria from industrial effluents with potential use in bioremediation. The decolorizing activity of the bacteria was measured using a photo electric colorimeter after aerobic incubation in different time intervals of the isolates. Environmental parameters such as pH, temperature, initial dye concentration and inoculum size were optimized using mineral salt medium containing different concentration of Crystal Violet dye. Complete decolorizing efficiency was observed in a mineral salt medium containing up to 150 mg/l of Crystal Violet dye by 10% (v/v) inoculums of Enterobacter sp. CV–S1 tested under 72 h of shaking incubation at temperature 35 °C and pH 6.5. Newly identified bacteria Enterobacter sp. CV–S1, confirmed by 16S ribosomal RNA sequencing, was found as a potential bioremediation biocatalyst in the aerobic degradation/de-colorization of Crystal Violet dye. The efficiency of degrading triphenylmethane dye by this isolate, minus the supply of extra carbon or nitrogen sources in the media, highlights the significance of larger-scale treatment of textile effluent.
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Christophers, Meg, Lauren Heng, and Nicholas Heng. "Nisin E, a New Nisin Variant Produced by Streptococcus equinus MDC1." Applied Sciences 13, no. 2 (January 16, 2023): 1186. http://dx.doi.org/10.3390/app13021186.
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Members of the genus Streptococcus inhabit a variety of sites in humans and other animals and some species are prolific producers of proteinaceous antibiotics (bacteriocins). As little is known about (i) streptococci inhabiting domestic pets, and (ii) whether novel bacteriocin-producing streptococci can be isolated from domestic pets, the aim of this study is to address these gaps in the research literature. In this study, Streptococcus equinus MDC1, isolated from a healthy dog, was found to exhibit potent antibacterial activity against Micrococcus luteus in a simultaneous antagonism assay, suggesting that strain MDC1 produces a lantibiotic bacteriocin. The inhibitory activity spectrum of S. equinus MDC1, determined using agar-based deferred antagonism assays against >70 indicator strains, was found to be similar to that of nisin U (a lantibiotic produced by Streptococcus uberis). However, the spectra of the two bacteriocins differed by 23 strains, mainly with the MDC1 bacteriocin having no inhibitory activity towards certain streptococci of human origin (e.g., Streptococcus gordonii, Streptococcus anginosus, Streptococcus salivarius). The genome of S. equinus MDC1, which was sequenced completely using single-molecule real-time (SMRT) next-generation DNA sequencing technology, comprises a single 1,936,555-basepair chromosome containing seven copies of the ribosomal RNA operon, 69 tRNA genes and nearly 1900 putative coding sequences. Analysis of the MDC1 genome sequence using the bacteriocin detection algorithms BAGEL4 and antiSMASH revealed the location of a 13,164-basepair 11-gene locus, designated nmd, which encoded a mature nisin E peptide that differed from nisin U by only two amino acids (Ile15→Ala and Leu21→Ile) and an extra C-terminal asparagine residue, and the proteins required for post-translational modification of the bacteriocin, processing, export, and producer immunity. Despite the high homology (90.6% identity, 93.8% similarity) between nisin E and nisin U, there was considerably less homology (47.4–76.3% identity, 68.4–88.8% similarity) between the other proteins encoded by their respective biosynthetic loci. This new natural variant of nisin, called nisin E, represents the first nisin variant to be reported for S. equinus; additionally, its differences with nisin U may provide some insight into the amino acids that influence bacteriocin potency and killing spectrum.
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Jägerback, S., A. Gomez, and I. Parodis. "OP0052 PREDICTORS OF RENAL FLARES IN SYSTEMIC LUPUS ERYTHEMATOSUS: A POST-HOC ANALYSIS OF FOUR PHASE III CLINICAL TRIALS OF BELIMUMAB." Annals of the Rheumatic Diseases 82, Suppl 1 (May 30, 2023): 34.1–34. http://dx.doi.org/10.1136/annrheumdis-2023-eular.6142.
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BackgroundIn patients with systemic lupus erythematosus (SLE), renal involvement is associated with high morbidity, and renal flares are major contributors to poor long-term prognosis. Identification of patients at risk of developing renal flares despite immunosuppressant therapy is imperative to optimise management.ObjectivesTo identify predictors of renal flares in patients receiving treatment for active extra-renal SLE.MethodsData from BLISS-52 (NCT00424476), BLISS-76 (NCT00410384), BLISS Northeast Asia (NEA;NCT01345253), and BLISS-SC (NCT01484496) were used (N=3225). The trials included patients with active, seropositive SLE and excluded active severe renal SLE. Participants were assigned to belimumab or placebo, on top of non-biologic standard therapy. We investigated anti-dsDNA, anti-Sm, anti-ribosomal P, and anti-cardiolipin (aCL) antibodies, low C3 and low C4 levels, B cell activating factor (BAFF), serum albumin, serum creatinine, and proteinuria at baseline as potential predictors of renal flares during a 52-week follow-up. We used Cox regression models to evaluate traditional disease features as predictors of renal flares in the pooled trial population. We also performed subgroup analysis of belimumab and placebo recipients. Covariates in the adjusted models included age, sex, ethnicity, body mass index, organ damage, baseline extra-renal activity (SLEDAI-2K score excluding renal and immunological descriptors), current or former renal SLE history (renal BILAG A–D), baseline use of glucocorticoids, antimalarials, and immunosuppressants, and use of belimumab.ResultsThe mean age of the study population was 36.7 years, 94% were women, 54.6% had current or former renal involvement at baseline, and 192 developed a renal flare after a median follow-up time of 197 (IQR: 85–330) days from baseline. Patients with current or former renal involvement at baseline displayed a >9-fold increased hazard to develop a new renal flare (HR: 9.4; 95% CI: 5.0–17.7; P<0.001). In the pooled study population, baseline serum albumin (adjusted HR 0.9; 95% CI: 0.9–0.9; P<0.001), proteinuria (adjusted HR: 1.3; 95% CI: 1.2–1.4; P<0.001), and low C3 levels (adjusted HR: 1.8; 95% CI: 1.3–2.5; P<0.001) were robust determinants of subsequent renal flare occurrence; similar associations were found in the belimumab and placebo subgroups. Furthermore, we observed an association between anti-dsDNA positivity and renal flare development in univariable models (HR: 2.1; 95% CI: 1.4–3.2; P<0.001 in the pooled population), which attenuated in multivariable models (Figure 1). Positive levels of anti-Sm antibodies were associated with renal flare occurrence in the placebo (adjusted HR: 2.9; 95% CI: 1.5–5.6; P=0.002) but not in the belimumab subgroup, whereas anti-ribosomal P antibodies were associated with renal flare development in belimumab-treated (HR: 2.8; 95% CI: 1.5–5.0; P<0.001) but not in placebo-treated patients. Finally, positive levels of aCL antibodies (any isotype) predicted renal flare development in the belimumab group (adjusted HR: 1.8; 95% CI: 1.1–2.8; P=0.020) but yielded a negative association in the placebo group (adjusted HR: 0.4; 95% CI: 0.2–0.9; P=0.028).ConclusionCurrent or former renal involvement, high baseline proteinuria levels, hypoalbuminaemia, and C3 consumption were robust determinants of imminent renal flares. Beyond anti-dsDNA, anti-ribosomal P and aCL antibody positivity may prove valuable early signals of imminent renal flares in patients treated with belimumab. Anti-Sm positivity predicted imminent renal flares in patients treated with non-biological standard therapy, but not in belimumab-treated patients, assumably due to benefit conferred from belimumab in anti-Sm positive individuals, as shown previously [1].Reference[1]Parodis I, et al. Int J Mol Sci. 2020; 21(10):3463Figure 1.Cox regression models evaluating traditional markers as predictors of renal flares in patients with SLE treated with non-biological standard therapy with or without add-on belimumab.AcknowledgementsThe authors would like to thank GlaxoSmithKline for providing data through the CSDR consortium as well as all patients with SLE who participated in the trials.Disclosure of InterestsSandra Jägerback: None declared, Alvaro Gomez: None declared, Ioannis Parodis Grant/research support from: I.P. has received research funding and/or honoraria from Amgen, AstraZeneca, Aurinia Pharmaceuticals, Elli Lilly and Company, Gilead Sciences, GlaxoSmithKline, Janssen Pharmaceuticals, Novartis, Otsuka Pharmaceutical, and F. Hoffmann-La Roche AG.
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Lento, William, Wei Huang, Phuong Doan, Nelson J. Chao, and Luigi Racioppi. "Calcium Calmodulin Dependent Kinase Kinase 2 Regulates Hematopoietic Stem Cell Regeneration and Quiescence." Blood 124, no. 21 (December 6, 2014): 1571. http://dx.doi.org/10.1182/blood.v124.21.1571.1571.
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Abstract Extracellular free calcium (Ca2+) is the most abundant signaling molecule in the hematopoietic stem cell (HSC) niche, and intracellular calcium is an important second messenger controlling critical functions in HSCs. Accordingly, Ca2+ is a master regulator of HSC biology, and nodes of the Ca2+ signaling network are emerging as critical components of the molecular machinery governing HSC regeneration and quiescence. Ca2+ controls many cell functions by forming a complex with Calmodulin (CaM), which binds and activates a family of Calcium/Calmodulin dependent kinase (CaMK) that includes CaMKI, CaMKII, CaMKIV, CaMKK1 and CaMKK2. We have previously investigated the function of CaMKK2 in blood cells and established this protein as a critical component of the calcium signaling pathway that regulates granulopoiesis and macrophage activation. Here, we investigated the function of CaMKK2 in the regenerative response of HSCs. To determine the expression of CaMKK2 under homeostatic conditions, we examined transgenic reporter mice and identified robust reporter activity in primitive long-term hematopoietic stem cells, but reduced signal in the majority of lineage positive blood and bone marrow cells. To establish whether CaMKK2 has a functional role in controlling hematopoiesis and HSC self-renewal, we examined hematopoietic regeneration in mice deficient for CaMKK2. We demonstrate that Camkk2 -/- mice have accelerated bone marrow and peripheral blood regeneration following hematopoietic injury. Camkk2 -/- HSCs showed increased proliferative capacity in vivo and mobilized into the peripheral blood to establish extra-medullary hematopoiesis during regeneration. To identify the proximal target of CaMKK2, we assessed the phosphorylation status of CaMKI, CaMKIV and adenosine monophosphate activated protein kinase (AMPK), which are known targets of CaMKK2. Our results indicate Camkk2 -/- stem and progenitor cells (HSPC) fail to accumulate phospho-AMPK in response to ionizing radiation. Since AMPK is a negative regulator of the mammalian target of rapamycin (mTOR) pathway, we also analyzed the levels of phospho-ribosomal 6 protein (rpS6), which is a distal target of the mTOR cascade that positively regulates cell size and proliferation. We found that irradiated Camkk2 -/- HSPCs accumulate higher levels of phospho-rpS6 compared to wild type cells. This finding implicates CaMKK2 as a critical component of a negative regulatory circuit that links calcium signaling to AMPK activation and cell proliferation in HSPC. Cumulatively, our data demonstrate that CaMKK2 regulates HSC function and suggests CaMKK2 inhibition is a novel approach to stem cell expansion for clinical therapy. Disclosures No relevant conflicts of interest to declare.
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Pospisilova, Dagmar, Dusan Holub, Zuzana Zidova, Barbora Ludikova, Lucie Sulovska, Vladimir Divoky, and Monika Horvathova. "Erythropoiesis and Iron Metabolism In Diamond-Blackfan Anemia." Blood 122, no. 21 (November 15, 2013): 2478. http://dx.doi.org/10.1182/blood.v122.21.2478.2478.
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Abstract Diamond-Blackfan anemia (DBA) is a rare congenital red cell aplasia characterized by macrocytic anemia, reticulocytopenia and reduced number of erythroblasts in the bone marrow. Etiology and symptoms of DBA are closely associated with mutations of genes coding for 12 ribosomal proteins. Approximately 40% of patients are dependent on regular transfusions. In chronically transfused DBA patients, severe iron overload with tissue hemosiderosis with the need for iron chelation develops and has a substantial impact on morbidity and mortality of DBA patients. Liver is the most affected organ, but extra-hepatic iron accumulation, although less well documented, appears to occur early and at high frequency. Despite these facts a detailed analysis of iron metabolism in DBA is missing. We therefore aimed to determine selected markers of erythropoid activity and iron metabolism including the levels of the key regulator of iron homeostasis, hepcidin, in 14 DBA patients from the Czech National DBA Registry. Ten patients receive regular transfusions, two are treated with steroids and two are in the remission. None of the patients had signs of an inflammatory process at the time of the examination. Following markers of iron metabolism were analysed: iron, total iron binding capacity, transferrin saturation, ferritin and soluble transferrin receptor (TfR). Serum hepcidin was measured by proteomic analysis. Levels of rowth differentiation factor 15 (GDF 15), aputative marker of erythroid activity, were measured by ELISA. Pearls’ staining was used for the liver iron detection. In all transfusion dependent patients, low levels of soluble TfR and reduced number of erythroblasts in the bone marrow confirm severally suppressed erythropoiesis which corresponded with dramatically elevated serum erythropoietin (EPO) levels. Analysis of iron parameters showed increased transferrin saturation and high ferritin levels. The two patients who are currently in the remission had near normal blood counts and iron parameters. Liver biopsy on 5 selected patients revealed excessive iron accumulation in both liver hepatocytes and macrophages which can be attributed to increased iron uptake and non-effective erythrocytes-derived iron recycling, respectively. Measurement of hepcidin levels showed significant elevation in DBA cohort in comparison with healthy controls (p>0.0005). The highest hepcidin was detected for transfusion dependent patients, the lowest (near normal) for patients in remission. As erythropoiesis is known to produce a signal for hepcidin suppression, patients in remission with restored erythropoietic activity are likely able to attenuate hepcidin expression and increase the pool of iron available for improved erythropoiesis. On the other hand repeated blood transfusions contribute to the suppression of erythropoiesis thus likely relieving hepcidin synthesis and worsening iron recycling. We also found that elevated hepcidin positively correlated with ferritin levels. No correlation was detected with EPO or GDF15, the putative negative regulator of hepcidin production. These results indicate that EPO is an indirect suppressor of hepcidin synthesis and that GDF15 possibly plays a hepcidin-regulatory role in the disease states associated with ineffective erythropoiesis but not in DBA. In conclusion we propose that in DBA patients iron overload develops as a consequence of the combination of repeated transfusions and absent or reduced erythropoiesis in the bone marrow. At the systemic level the increased hepcidin promotes iron retention in macrophages and thus is responsible for impaired iron recycling. Acknowledgments Grant support: Ministry of Health, Czech Republic, grant No. NT11059 to DP and NT/13587 to VD, Czech Grant Agency, grant No. P305/11/1745, and Internal Grant of Palacky University Olomouc (LF_2013_010). We thank dr. Thomas Ganz for validation of our HPLC-MS-based hepcidin measurements. Disclosures: No relevant conflicts of interest to declare.
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Meng, F., B. Forrester-Gauntlett, H. Henderson, and B. Oback. "81 JAK-STAT SIGNALLING IS CRITICAL FOR INNER CELL MASS DEVELOPMENT IN BOVINE BLASTOCYSTS." Reproduction, Fertility and Development 27, no. 1 (2015): 133. http://dx.doi.org/10.1071/rdv27n1ab81.
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The inner cell mass (ICM) of mammalian blastocysts comprises 2 transient lineages, namely hypoblast and epiblast, which develop into extra-embryonic and embryonic tissues, respectively. In the mouse, epiblast cells autocrinally secrete fibroblast growth factor (FGF) to induce hypoblast differentiation, and pharmacological FGF/mitogen-activated protein kinase (MAPK) signal inhibition converts all ICM cells into epiblast. We conducted a chemical screen for additional signal enhancers of epiblast identity in bovine Day 8 blastocysts. From the morula stage onwards, in vitro-fertilised (IVF) embryos were cultured in the presence of 9 small molecule inhibitors, targeting 9 principal signal pathway components. Inhibitors included SB431542, LDN193189, BIBF1120, Forskolin, BI-D1870, A66/TGX 221/ZSTK474, and AZD1480, targeting TGFβ-RI, BMP-RI, VEGFR/PDGFR/FGFR, adenylate cyclase, ribosomal S6 kinase (RSK), PI3K, and JAK2 signalling, respectively. Using (1) blastocyst quality (by morphological grading), (2) cell numbers (by differential stain), and (3) lineage-specific candidate gene expression (by quantitative PCR) as readouts, we sought to identify positive and negative regulators of ICM development and lineage determination. Based on our previous digital mRNA profiling data (McLean et al. 2014 Biol. Reprod., in press), we selected discriminatory epiblast-specific (FGF4, NANOG) and hypoblast-specific (PDGFRα, SOX17) markers for qPCR analysis. Each inhibitor was compared, alone or in combination, to an appropriately diluted dimethylsulfoxide (DMSO) vehicle control in at least 3 biological replicates. Statistical significance was determined using a generalised linear mixed model with binomial distribution and logit link for developmental data and REML for log cell counts and log gene expression data, applying fixed treatment effects and random run and sample within run effects. Blocking TGFβ1-, BMP- or VEGF-/PDGF-/FGF-signalling did not affect blastocyst development, ICM v. trophectoderm (TE) cell numbers, or gene expression. Repression of PI3K signals via AG66 and TGX, but not ZSTK alone, modestly decreased grade 1–2 blastocyst development (P < 0.05) but had no effect on cell numbers or gene expression. Stimulating adenylate cyclase activity increased NANOG levels (2.5-fold; P < 0.05), while RSK inhibition reduced FGF4 and PDGFRα expression (4-fold and 2-fold, respectively; P < 0.05). Suppressing JAK-STAT signalling, on the other hand, consistently compromised grade 1–2 blastocyst development and ICM numbers relative to DMSO controls (18/235 = 7% v. 59/159 = 29%, n = 5 IVF runs; 12 v. 47 ICM cells, N = 25 and N = 7 embryos counted, respectively; P < 0.0001). Epiblast and hypoblast markers were up to 40-fold reduced (FGF4, NANOG, SOX17; P < 0.0001) or completely abolished (PDGFRα; P < 0.0001). This effect was specific to the ICM because TE numbers and TE-specific gene expression (CDX2, KTR8) were not significantly altered. In summary, we have established Day 8 blastocysts as a useful chemical screening platform and demonstrated that bovine ICM development critically depends on JAK-STAT signalling.
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Sim, Edmund Ui-Hang, Choon-Weng Lee, and Kumaran Narayanan. "The roles of ribosomal proteins in nasopharyngeal cancer: culprits, sentinels or both." Biomarker Research 9, no. 1 (June 30, 2021). http://dx.doi.org/10.1186/s40364-021-00311-x.
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AbstractRibosomal protein genes encode products that are essential for cellular protein biosynthesis and are major components of ribosomes. Canonically, they are involved in the complex system of ribosome biogenesis pivotal to the catalysis of protein translation. Amid this tightly organised process, some ribosomal proteins have unique spatial and temporal physiological activity giving rise to their extra-ribosomal functions. Many of these extra-ribosomal roles pertain to cellular growth and differentiation, thus implicating the involvement of some ribosomal proteins in organogenesis. Consequently, dysregulated functions of these ribosomal proteins could be linked to oncogenesis or neoplastic transformation of human cells. Their suspected roles in carcinogenesis have been reported but not specifically explained for malignancy of the nasopharynx. This is despite the fact that literature since one and half decade ago have documented the association of ribosomal proteins to nasopharyngeal cancer. In this review, we explain the association and contribution of dysregulated expression among a subset of ribosomal proteins to nasopharyngeal oncogenesis. The relationship of these ribosomal proteins with the cancer are explained. We provide information to indicate that the dysfunctional extra-ribosomal activities of specific ribosomal proteins are tightly involved with the molecular pathogenesis of nasopharyngeal cancer albeit mechanisms yet to be precisely defined. The complete knowledge of this will impact future applications in the effective management of nasopharyngeal cancer.
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Shekhtman, Alexander, Chris DeMott, Subhabrata Majumder, and Sergey Reverdatto. "Extra‐ribosomal function of bacterial ribosomes: Modulation of enzyme activities." FASEB Journal 31, S1 (April 2017). http://dx.doi.org/10.1096/fasebj.31.1_supplement.759.1.
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The intracellular concentration of bacterial ribosome is linearly proportional to the growth rate and can occupy up to 20% of the cell volume or about 50 mg/mL. This high concentration facilitates weak binding between cytosolic proteins and ribosomes and can affect protein biochemistry. By using a combination of in‐cell and in vitro biophysical techniques, we show that adenylate kinase (ADK) and dihydrofolate reductase (DHFR) bind to ribosomes via specific interaction surfaces, and the respective co‐factors ATP and NADPH also bind to ribosomes both specifically and non‐specifically. As a consequence, ribosomes modulate the enzymatic activity of ADK and DHFR by interfering with substrate availability. Ribosome binding also impedes protein diffusion, an important determinant for reaction rates. Using fluorescence recovery after bleaching (FRAP), we show that green fluorescent protein (GFP) diffusion is significantly slower in the presence of ribosomes in vitro, comparable to that observed intracellularly. These results strongly suggest that ribosomes play a previously under‐appreciated, non‐translational role in regulating the cellular activity of enzymes.Support or Funding InformationThis work was supported by National Institutes of Health Grant 5R01GM085006 to A.S.
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Pecoraro, Annalisa, Pietro Carotenuto, Giulia Russo, and Annapina Russo. "Ribosomal protein uL3 targets E2F1 and Cyclin D1 in cancer cell response to nucleolar stress." Scientific Reports 9, no. 1 (October 28, 2019). http://dx.doi.org/10.1038/s41598-019-51723-7.
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Abstract Several experimental strategies in the treatment of cancer include drug alteration of cell cycle regulatory pathways as a useful strategy. Extra-ribosomal functions of human ribosomal protein L3 (uL3) may affect DNA repair, cell cycle arrest and apoptosis. In the present study, we demonstrated that uL3 is required for the activation of G1/S transition genes. Luciferase assays established that uL3 negatively regulates the activity of E2F1 promoter. Induced ribosome-free uL3 reduces Cyclin D1 mRNA and protein levels. Using protein/protein immunoprecipitation methods, we demonstrated that uL3 physically interacts with PARP-1 affecting E2F1 transcriptional activity. Our findings led to the identification of a new pathway mediated by uL3 involving E2F1 and Cyclin D1 in the regulation of cell cycle progression.
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Clasen, Sara J., Wei Shao, He Gu, and Peter J. Espenshade. "Prolyl dihydroxylation of unassembled uS12/Rps23 regulates fungal hypoxic adaptation." eLife 6 (October 30, 2017). http://dx.doi.org/10.7554/elife.28563.
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The prolyl-3,4-dihydroxylase Ofd1 and nuclear import adaptor Nro1 regulate the hypoxic response in fission yeast by controlling activity of the sterol regulatory element-binding protein transcription factor Sre1. Here, we identify an extra-ribosomal function for uS12/Rps23 central to this regulatory system. Nro1 binds Rps23, and Ofd1 dihydroxylates Rps23 P62 in complex with Nro1. Concurrently, Nro1 imports Rps23 into the nucleus for assembly into 40S ribosomes. Low oxygen inhibits Ofd1 hydroxylase activity and stabilizes the Ofd1-Rps23-Nro1 complex, thereby sequestering Ofd1 from binding Sre1, which is then free to activate hypoxic gene expression. In vitro studies demonstrate that Ofd1 directly binds Rps23, Nro1, and Sre1 through a consensus binding sequence. Interestingly, Rps23 expression modulates Sre1 activity by changing the Rps23 substrate pool available to Ofd1. To date, oxygen is the only known signal to Sre1, but additional nutrient signals may tune the hypoxic response through control of unassembled Rps23 or Ofd1 activity.
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Lee, Bong-Woo, Eui-Jong Kwon, Youngjae Park, Jennifer Jooha Lee, Ji Hyeon Ju, Sung-Hwan Park, and Seung-Ki Kwok. "Predictors for future development of systemic lupus erythematosus in Korean Sjögren’s syndrome patients." Lupus, September 26, 2023. http://dx.doi.org/10.1177/09612033231204067.
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Objective This study determined the impact of demographic factors, clinical manifestations, disease activity, and serological tests at baseline on future SLE development in Sjögren’s syndrome (SS) patients. Methods This retrospective study assessed 1,082 SS patients without other autoimmune diseases at baseline who visited our hospital between January 2012 and March 2021. We analyzed demographic features, extra-glandular manifestations (EGMs), clinical indices, and laboratory values at baseline between the two groups divided per future SLE development (SS/SLE group vs SS group). The probability and predictors of SLE development in SS patients were estimated using the Kaplan–Meier method and Cox proportional hazards models. Results The median follow-up duration was 1083.5 days. Forty-nine patients (4.5%) developed SLE that met the 2012 Systemic Lupus International Collaborating Clinics or 2019 EULAR/ACR classification criteria. The baseline EULAR SS disease activity index (ESSDAI) score was significantly higher in the SS/SLE group ( p < .001). The SS/SLE group had more lymphadenopathy and renal involvement ( p = .015 and p = .017, respectively). Shorter SS disease duration (<3 years) (hazard ratio [HR] = 2.12, p = .0328), high ESSDAI (HR = 8.24, p < .0001), leukopenia (HR = 4.17, p = .0005), thrombocytopenia (HR = 3.38, p = .0059), hypocomplementemia (HR = 29.06, p<.0001), and positive for anti-dsDNA (HR = 13.70, p < .0001), anti-ribonucleoprotein (RNP) (HR = 3.82, p = .0027), and anti-ribosomal P (HR = 6.70, p = .0002) at baseline were SLE development predictors in SS patients. Conclusion Shorter disease duration and higher disease activity of SS at baseline may be risk factors for future SLE development. Serologic predictors of SLE development are hypocomplementemia, leukopenia, thrombocytopenia, and positivity for anti-dsDNA, anti-RNP, and anti-ribosomal P antibodies. If the above factors are observed, close monitoring will be necessary during the follow-up period, considering the possibility of future SLE development.
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Katanaev, Vladimir L., Mikhail Kryuchkov, Volodymyr Averkov, Mikhail Savitsky, Kseniya Nikolaeva, Nadezhda Klimova, Sergei Khaustov, and Gonzalo P. Solis. "HumanaFly: high-throughput transgenesis and expression of breast cancer transcripts in Drosophila eye discovers the RPS12-Wingless signaling axis." Scientific Reports 10, no. 1 (December 2020). http://dx.doi.org/10.1038/s41598-020-77942-x.
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AbstractDrosophila melanogaster has been a model for multiple human disease conditions, including cancer. Among Drosophila tissues, the eye development is particularly sensitive to perturbations of the embryonic signaling pathways, whose improper activation in humans underlies various forms of cancer. We have launched the HumanaFly project, whereas human genes expressed in breast cancer patients are screened for their ability to aberrate development of the Drosophila eye, hoping to thus identify novel oncogenes. Here we report identification of a breast cancer transgene, which upon expression in Drosophila produces eye malformation similar to the famous Glazed phenotype discovered by Thomas Morgan and decades later dissected to originate from mis-expression of Wingless (Wg). Wg is the ortholog of human Wnt proteins serving as ligands to initiate the developmental/oncogenic Wnt signaling pathway. Through genetic experiments we identified that this transgene interacted with the Wg production machinery, rather than with Wg signal transduction. In Drosophila imaginal discs, we directly show that the transgene promoted long-range diffusion of Wg, affecting expression of the Wg target genes. The transgene emerged to encode RPS12—a protein of the small ribosomal subunit overexpressed in several cancer types and known to also possess extra-ribosomal functions. Our work identifies RPS12 as an unexpected regulator of secretion and activity of Wnts. As Wnt signaling is particularly important in the context of breast cancer initiation and progression, RPS12 might be implicated in tumorigenesis in this and other Wnt-dependent cancers. Continuation of our HumanaFly project may bring further discoveries on oncogenic mechanisms.