L-leucine improves the anemia and developmental defects associated with Diamond-Blackfan anemia and del(5q) MDS by activating the mTOR pathway

Abstract Haploinsufficiency of ribosomal proteins (RPs) has been proposed to be the common basis for the anemia observed in Diamond-Blackfan anemia (DBA) and myelodysplastic syndrome with loss of chromosome 5q [del(5q) MDS]. We have modeled DBA and del(5q) MDS in zebrafish using antisense morpholinos to rps19 and rps14, respectively, and have demonstrated that, as in humans, haploinsufficient levels of these proteins lead to a profound anemia. To address the hypothesis that RP loss results in impaired mRNA translation, we treated Rps19 and Rps14-deficient embryos with the amino acid L-leucine, a known activator of mRNA translation. This resulted in a striking improvement of the anemia associated with RP loss. We confirmed our findings in primary human CD34+ cells, after shRNA knockdown of RPS19 and RPS14. Furthermore, we showed that loss of Rps19 or Rps14 activates the mTOR pathway, and this is accentuated by L-leucine in both Rps19 and Rps14 morphants. This effect could be abrogated by rapamycin suggesting that mTOR signaling may be responsible for the improvement in anemia associated with L-leucine. Our studies support the rationale for ongoing clinical trials of L-leucine as a therapeutic agent for DBA, and potentially for patients with del(5q) MDS.

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L-Leucine Improves the Anemia of DBA and the 5q- Syndrome Via Activation of the mTOR Pathway in a p53-Independent Manner

Blood ◽

10.1182/blood.v120.21.1257.1257 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1257-1257

Author(s):

Nirmalee Abayasekara ◽

Anupama Narla ◽

Slater Hurst ◽

Hong Sun ◽

Maria Virgilio ◽

...

Keyword(s):

Myelodysplastic Syndrome ◽

Ribosomal Proteins ◽

Mrna Translation ◽

Mtor Pathway ◽

Zebrafish Embryos ◽

P53 Expression ◽

Human Cd34 ◽

Chromosome 5Q ◽

Cd34 Cells ◽

Shrna Knockdown

Abstract Abstract 1257 Haploinsufficiency of ribosomal proteins (RP) has been shown to be the common basis for the anemia observed in ribosomopathies such as Diamond-Blackfan anemia (DBA) and myelodysplastic syndrome with loss of chromosome 5q (del(5q) MDS). DBA is a congenital bone marrow failure syndrome characterized by a profound macrocytic anemia. More than half the patients with DBA have been shown to have a heterozygous loss of an RP gene, with RPS19 being the most frequently mutated. The “5q- syndrome” is a subtype of myelodysplastic syndrome (MDS) also characterized by severe anemia that is caused by heterozygous loss of the RPS14 gene on chromosome 5q. The p53 pathway is known to play a critical role in the pathophysiology of the ribosomopathies. The leading hypothesis is that ribosomal haploinsufficiency leads to disrupted ribosome biogenesis with an accumulation of free ribosomal proteins that bind MDM2. MDM2 is an E3 Ubiquitin ligase that normally binds to and targets p53 for proteosomal degradation. The consequent accumulation of p53 leads to cell cycle arrest and apoptosis, which ultimately results in anemia. Several animal models have shown that the anemia associated with RP haploinsufficiency is almost completely alleviated in a p53 null background. However, we and others have shown that p53-independent pathway(s) also contribute to the anemia associated with RP haploinsufficiency. We have previously modeled DBA and del (5q) MDS in zebrafish using antisense morpholinos to rps19 and rps14 respectively, and have demonstrated that, as in humans, haploinsufficient levels of these proteins lead to a profound anemia. We have further demonstrated that treatment of Rps19 and Rps14 deficient embryos with the amino acid L-Leucine, a known activator of mRNA translation, results in a marked improvement in anemia. This observation was confirmed in primary human CD34+ cells, following shRNA knockdown of RPS19 and RPS14. Furthermore, we showed that L-leucine treatment activates the mTOR pathway in zebrafish embryos deficient in Rps19 or Rps14. In order to determine if the effect of L-Leucine on RP deficient erythroid cells is p53 dependent, we injected rps19 and rps14 morpholinos into zebrafish embryos and treated them with L-Leucine. Total RNA was collected 48hpf and evaluated for expression of p53 by qPCR analysis. As expected, the expression of p53 and its downstream targets (p21 and PUMA) were upregulated in Rps14 and Rps19 deficient embryos. P53 expression levels remained elevated even after L-Leucine treatment. Levels of p21, a direct transcriptional target of p53, remained unchanged in L-Leucine treated RP deficient zebrafish embryos; however, expression of PUMA increased following L-Leucine treatment. The expression of the PUMA gene has previously been shown to have a p53-independent regulatory component. Preliminary studies in the A549 cell line, which harbors wild type p53, also showed increased levels of p53 expression upon shRNA mediated downregulation of both RPS19 and RPS14, which remained unaltered following L-Leucine treatment. These observations are currently being confirmed in primary human CD34+ cells, following shRNA knockdown of RPS19 and RPS14. Our preliminary studies show that the effect of L-Leucine in improving the anemia in models of DBA and del(5q) MDS occurs independently of p53. This supports our hypothesis that the erythroid phenotype in these disorders has a p53-independent component. Our finding that L-Leucine treated RP deficient cells are likely to express elevated rather than diminished levels of p53 in spite of improved anemia also has important implications for the clinical management of patients, since p53 inactivation is associated with tumor growth. A trial using L-Leucine for patients with DBA will be opening soon in the United States. Disclosures: Ebert: Celgene: Consultancy; Genoptix: Consultancy.

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P53 is Activated without RPL11 Upregulation in Diamond-Blackfan Anemia,

Blood ◽

10.1182/blood.v118.21.3432.3432 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3432-3432

Author(s):

Hong-Yan Du ◽

M. Tarek Elghetany ◽

Blanche P Alter ◽

Akiko Shimamura

Keyword(s):

Bone Marrow ◽

Ribosomal Protein ◽

Ribosomal Proteins ◽

Mrna Levels ◽

Protein Levels ◽

Diamond Blackfan Anemia ◽

Human Cd34 ◽

Cd34 Cells ◽

P53 Activation ◽

Ribosomal Stress

Abstract Abstract 3432 Diamond-Blackfan anemia (DBA) is an autosomal dominantly inherited bone marrow failure syndrome characterized by red cell aplasia, physical anomalies, and cancer predisposition. DBA is caused by mutations resulting in haploinsufficiency of genes encoding ribosomal proteins. p53 is activated in the erythroid lineage following reduction of ribosomal protein expression; however the mechanism whereby ribosomal stress results in p53 activation in DBA remains unclear. RPL11 has been proposed to play a central role in p53 activation following ribosomal stress. Reduced expression of individual small ribosomal subunit proteins in a tumor cell line resulted in increased translation of RPL11. Excess free RPL11 can bind and inactivate HDM2, an E3 ubiquitin ligase targeting p53 for degradation. The recent demonstration that cellular responses to ribosomal perturbations vary widely between different tissues raised the question of whether RPL11 upregulation contributes to p53 activation following ribosomal stress in hematopoietic progenitors. To address this question, we modeled DBA in human CD34+ cells. Since RPS19 is the most commonly mutated gene in DBA, we used lentiviral vectors expressing short hairpin RNAs to knock down RPS19 expression in primary human CD34+ cells. RPS19 protein levels were reduced to about 50% of control levels in a manner reflecting the haploinsufficient state in DBA. RPS19 depletion resulted in elevated p53 protein levels and increased mRNA levels of p21, a transcriptional target of p53. Total p53 mRNA levels and p53 mRNA translational activity remained unchanged consistent with a post-transcriptional mechanism for p53 activation. Although total RPL11 mRNA levels were not diminished following RPS19 depletion, RPL11 protein levels were significantly decreased consistent with post-transcriptional downregulation. Depletion of RPS19 in human CD34+ cells did not affect polysome loading of RPL11 mRNA. Reduction of additional ribosomal proteins also accompanied RPS19 knockdown consistent with coordinate regulation of multiple ribosomal protein levels. Corticosteroids, which improve anemia in the majority of DBA patients, did not prevent p53 activation, nor did this improve RPS19 or RPL11 protein levels. Expression of p53 was also assessed in bone marrow biopsy slides from 26 DBA patients with the following genotypes: RPS19 (18), RPS24 (2), RPS26 (2), RPS10 (1), RPS17 (1), RPS7 (1), and RPL11 (1). p53 was over-expressed in all but one patient (RPS26), and was clearly over-expressed in the DBA patient harboring the RPL11 mutation. In summary, we find that p53 activation in DBA does not require upregulation of RPL11 translation or elevated RPL11 protein levels. p53 activation persists in DBA caused by RPL11 deficiency. Corticosteroids do not improve ribosomal protein levels nor do they prevent p53 activation. Disclosures: No relevant conflicts of interest to declare.

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Tifab, a Novel Candidate Gene in Deletion Chromosome 5q, Contributes to Deregulation of NF-κB Signaling in MDS/AML.

Blood ◽

10.1182/blood.v120.21.2812.2812 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2812-2812

Author(s):

Melinda Varney ◽

Andres Jerez ◽

Jing Fang ◽

David Miller ◽

Lyndsey Bolanos ◽

...

Keyword(s):

Cell Cycle ◽

Research Funding ◽

Leukemia Cell ◽

Leukemic Cells ◽

Phase Cell ◽

Human Leukemia ◽

Hematopoietic Stem ◽

Human Cd34 ◽

Chromosome 5Q ◽

Cd34 Cells

Abstract Abstract 2812 Myelodysplastic syndromes (MDS) are hematologic disorders defined by blood cytopenias due to ineffective hematopoiesis, altered cytogenetics, and predisposition to acute myeloid leukemia (AML). The most common cytogenetic alteration in de novo and treatment-related MDS is deletion of chromosome 5q (del(5q)). There are two commonly deleted regions (CDR) mapped to chr 5q, however the gene(s) in these regions responsible for the manifestation of del(5q) MDS are not clearly defined. A search of annotated genes revealed that TRAF-interacting protein with forkhead-associated domain B (TIFAB), a known inhibitor of TRAF6 and a novel gene identified by an in silico search for TIFA-related genes, resides within the proximal CDR on band 5q31.1. We first determined whether TIFAB is expressed in normal hematopoietic stem/progenitor cell (HSPC) by qRT-PCR. We find that expression of TIFAB is enriched in human CD34+/CD38+ and mouse lineage-/cKit+ progenitors as compared to more differentiated populations, suggesting that it plays a role in normal HSPC function. To determine whether TIFAB is implicated in del(5q) MDS, we measured TIFAB expression in del(5q) MDS patients. According to a microarray analysis, TIFAB mRNA was significantly lower in CD34+cells isolated from MDS patients with del(5q) as compared with cells from MDS patients diploid at chr 5q (Pellagatti, et al., 2006). In an independent subset of patients, we confirmed that TIFAB expression was lower in marrow cells isolated from del(5q) MDS patients. Therefore, we hypothesize that TIFAB loss results in hematopoietic defects contributing to del(5q) MDS. To determine whether deletion of TIFAB affects hematopoiesis, we used lentiviral shRNAs to knockdown TIFAB mRNA in human cord blood CD34+ cells. To mimic haploinsufficiency of TIFAB in del(5q) MDS, we selected shRNAs that result in ∼50% knockdown of TIFAB mRNA and protein. Knockdown of TIFAB in human CD34+ cells results in increased survival, a competitive growth advantage, and altered hematopoietic progenitor function. Conversely, overexpression of TIFAB in human leukemia cell lines (THP1 and HL60) results in increased basal apoptosis, delayed G1/S-phase cell cycle progression, and impaired leukemic progenitor function in methylcellulose. Since TIFAB is predicted to regulate TRAF6, we examined the role of TIFAB on TRAF6 signaling. TIFAB suppressed TRAF6 lysine (K)-63 autoubiquitination (a measure of TRAF6 activity), and decreased total TRAF6 protein levels, suggesting that TIFAB may simultaneously inhibit TRAF6 function and protein expression. Consistent with this finding, TIFAB suppressed lipopolysaccharide-induced (TRAF6-dependent) NF-kB activation, but not TNF-induced (TRAF6-independent) NF-kB activation. TIFAB-mediated inhibition of TRAF6 also coincided with reduced phospho-IKK-beta (a measure of NF-kB activation) in leukemic cells. In summary, we have identified TIFAB as a novel del(5q) MDS/AML gene involved in regulating HSPC survival, progenitor function, and cell cycle. We propose that haploinsufficiency of TIFAB results in malignant clonal cell expansion and may contribute to the MDS/AML phenotype as a consequence of increased TRAF6-mediated activation of NF-kB. Disclosures: Maciejewski: NIH: Research Funding; Aplastic Anemia&MDS International Foundation: Research Funding.

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Lenalidomide and Dexamethasone Promote Erythropoiesis in Both Normal and RPS14 and RPS19 shRNA Infected Human CD34+ Cells: Implications for Therapy of Myelodysplastic Syndrome and Diamond-Blackfan Anemia.

Blood ◽

10.1182/blood.v114.22.1092.1092 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1092-1092

Author(s):

Anupama Narla ◽

Shilpee Dutt ◽

J. Randall McAuley ◽

Benjamin L. Ebert

Keyword(s):

Myelodysplastic Syndrome ◽

Bone Marrow Cells ◽

Absolute Number ◽

Erythroid Cells ◽

Erythroid Progenitor ◽

Diamond Blackfan Anemia ◽

Human Cd34 ◽

Cd34 Cells ◽

Dose Dependent

Abstract Abstract 1092 Poster Board I-114 Lenalidomide, a derivative of thalidomide, induces erythroid responses in patients with myelodysplastic syndrome while dexamethasone induces erythroid responses in patients with Diamond Blackfan anemia. In vitro, both lenalidomide and dexamethasone have been shown to stimulate erythropoiesis. In the present study, we explored the activity of lenalidomide and dexamethasone in stimulating erythroid differentiation of primary hematopoietic progenitor cells and CD34+ cells expressing RPS19 or RPS14 shRNAs. Both agents increase the absolute number of erythroid cells produced from normal human CD34+ bone marrow cells by 1.3 to 1.6-fold. Importantly, both lenalidomide and dexamethasone increased the diminished erythroid proliferative capacity of CD34+ cells expressing either RPS19 or RPS14 shRNAs. However, the drugs have distinct effects on the production of erythroid progenitor colonies, Blast Forming Units – Erythroid (BFU-E) and Colony Forming Units – Erythroid (CFU-E). Dexamethasone caused a dose-dependent and statistically significant increase in the number of BFU-E colonies by 2-fold, while it had little effect on CFU-E. In marked contrast, lenalidomide caused a dose-dependent and statistically significant increase in the number of CFU-E colonies by 2.5-fold but had no effect on BFU-E colonies. In addition, the combination of lenalidomide and dexamethasone had an additive effect on the production of erythroid cells and on erythroid colony formation. Our findings imply that lenalidomide and dexamethasone regulate different stages of erythropoiesis and lend support to the concept that combination therapy may be effective in minimizing the potential toxicity of these two drugs in the clinical management of patients. These findings have important implications for the treatment of patients with Myelodysplastic Syndrome as well as with Diamond Blackfan Anemia. Disclosures Off Label Use: Lenalidomide is approved for 5q- MDS. We are investigating its possible use in Diamond Blackfan Anemia.

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Ribosomopathies: New Therapeutic Perspectives

Cells ◽

10.3390/cells9092080 ◽

2020 ◽

Vol 9 (9) ◽

pp. 2080

Author(s):

Emilien Orgebin ◽

François Lamoureux ◽

Bertrand Isidor ◽

Céline Charrier ◽

Benjamin Ory ◽

...

Keyword(s):

Ribosomal Proteins ◽

Ribosome Biogenesis ◽

Genetic Disorders ◽

Cell Types ◽

Treacher Collins Syndrome ◽

Developmental Defects ◽

Diamond Blackfan Anemia ◽

New Therapeutic Approaches ◽

Multiple Treatments ◽

New Compounds

Ribosomopathies are a group of rare diseases in which genetic mutations cause defects in either ribosome biogenesis or function, given specific phenotypes. Ribosomal proteins, and multiple other factors that are necessary for ribosome biogenesis (rRNA processing, assembly of subunits, export to cytoplasm), can be affected in ribosomopathies. Despite the need for ribosomes in all cell types, these diseases result mainly in tissue-specific impairments. Depending on the type of ribosomopathy and its pathogenicity, there are many potential therapeutic targets. The present manuscript will review our knowledge of ribosomopathies, discuss current treatments, and introduce the new therapeutic perspectives based on recent research. Diamond–Blackfan anemia, currently treated with blood transfusion prior to steroids, could be managed with a range of new compounds, acting mainly on anemia, such as L-leucine. Treacher Collins syndrome could be managed by various treatments, but it has recently been shown that proteasomal inhibition by MG132 or Bortezomib may improve cranial skeleton malformations. Developmental defects resulting from ribosomopathies could be also treated pharmacologically after birth. It might thus be possible to treat certain ribosomopathies without using multiple treatments such as surgery and transplants. Ribosomopathies remain an open field in the search for new therapeutic approaches based on our recent understanding of the role of ribosomes and progress in gene therapy for curing genetic disorders.

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Treatment of Zebrafish Models of Ribosomopathies (Diamond Blackfan Anemia (DBA) and 5q- Syndrome) with L-Leucine Results In An Improvement of Anemia and Developmental Defects: Evidence for a Common Pathway?

Blood ◽

10.1182/blood.v116.21.195.195 ◽

2010 ◽

Vol 116 (21) ◽

pp. 195-195 ◽

Cited By ~ 1

Author(s):

Maria Virgilio ◽

Elspeth Payne ◽

Anupama Narla ◽

Hong Sun ◽

Barry Paw ◽

...

Keyword(s):

Bone Marrow ◽

Protein Synthesis ◽

Amino Acid ◽

Ribosomal Protein ◽

Mrna Translation ◽

Zebrafish Embryos ◽

Common Pathway ◽

Developmental Defects ◽

Diamond Blackfan Anemia ◽

Increased Risk

Abstract Abstract 195 A growing number of disorders associated with impaired ribosome biogenesis and function have been recently recognized and termed ribosomopathies. The first of these to be identified was Diamond Blackfan Anemia (DBA), a congenital autosomal dominant bone marrow failure syndrome of childhood manifested as profound macrocytic anemia. DBA is characterized by enhanced sensitivity of hematopoietic progenitors to apoptosis with evidence of stress erythropoiesis. In addition to bone marrow defects, DBA patients often have craniofacial, genitourinary, cardiac and limb abnormalities and are at an increased risk of developing hematopoietic malignancies and osteosarcoma. Twenty-five percent of patients with DBA have heterozygous mutations in the ribosomal protein S19 (RPS19) gene, which encodes a component of the 40S ribosomal subunit. Additionally, a growing percentage of DBA patients lacking a mutation in the RPS19 gene have been shown to have mutations in other ribosomal protein genes. A second ribosomopathy, 5q- syndrome is a subtype of myelodysplasia, with an erythroid phenotype strikingly similar to DBA. The erythroid phenotype of 5q- syndrome has been recently demonstrated to be attributable to acquired haploinsufficiency of the ribosomal protein RPS14 gene associated with clonal loss of the long arm of chromosome 5. In both DBA and 5q- syndrome, it is unclear why defects in ribosomal proteins, which would be expected to have widespread consequences, have such a specific effect on erythroid maturation. It has been demonstrated that the efficiency of mRNA translation is significantly depressed in cells derived from DBA patients, consistent with a pathogenic ribosomal defect. L-leucine is an essential branched chain amino acid that is known to modulate protein synthesis by enhancing translation. L-leucine has been used to treat DBA patients, and has been shown to lead to improvement in hemoglobin levels and to transfusion independence in some patients. Based on this observation we hypothesized that a common pathway associated with defective mRNA translation underlies both DBA and 5q- MDS, and that activation of translation by L-Leucine would alleviate the anemia associated with both ribosomopathies. In order to address this hypothesis, we have modeled DBA and 5q- MDS in zebrafish embryos using an antisense morpholino appraoach and have demonstrated that similar to the human diseases, Rps19 and Rps14 deficiency lead to defective erythropoiesis and to developmental abnormalities (specific to DBA). Treatment of Rps19 and Rps14 deficient embryos with L-Leucine resulted in partial reversal of both the anemia and the developmental defects. L-Leucine is thought to regulate protein synthesis by acting as a nutrient signal involving the mTOR (mammalian target of rapamycin) signaling pathway. It has been suggested that L-Leucine enhances translation by activating translation initiation factors and by specific up-regulation of the ribosomal protein S6 kinase. Activation of the mTOR pathway is currently being analyzed in the L-Leucine treated Rps19 and Rps14 deficient zebrafish embryos. Additionally, our observations are also being validated in in vitro human models for DBA and 5q-MDS using human hematopoietic progenitor CD34+ cells and shRNAs specific for Rps19 and Rps14 genes followed by L-Leucine treatment. Our studies should provide evidence for activation of pathways involved in mRNA translation and validate the use of the orally administered amino acid L-Leucine as a therapeutic agent in the treatment of DBA as well as 5q- syndrome without the side-effects associated with current therapies for both diseases. Disclosures: No relevant conflicts of interest to declare.

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An RNA interference model of RPS19 deficiency in Diamond-Blackfan anemia recapitulates defective hematopoiesis and rescue by dexamethasone: identification of dexamethasone-responsive genes by microarray

Blood ◽

10.1182/blood-2004-08-3313 ◽

2005 ◽

Vol 105 (12) ◽

pp. 4620-4626 ◽

Cited By ~ 65

Author(s):

Benjamin L. Ebert ◽

Michele M. Lee ◽

Jennifer L. Pretz ◽

Aravind Subramanian ◽

Raymond Mak ◽

...

Keyword(s):

Progenitor Cells ◽

Molecular Basis ◽

Erythroid Differentiation ◽

Erythroid Progenitor ◽

Diamond Blackfan Anemia ◽

Human Cd34 ◽

Erythroid Progenitor Cells ◽

Cd34 Cells ◽

Stimulation Of Erythropoiesis ◽

Short Hairpin Rnas

AbstractDiamond-Blackfan anemia (DBA), a congenital erythroblastopenia, is a model disease for the study of erythroid differentiation but is poorly understood. RPS19 is the only gene yet to have been associated with DBA, but its relevance to erythroid differentiation is unclear. The molecular basis for the stimulation of erythropoiesis by glucocorticoids in patients with DBA has not been identified. We demonstrate that targeted degradation of the RPS19 transcript, through retroviral expression of short hairpin RNAs (shRNAs), blocks the proliferation and differentiation of erythroid progenitor cells in cultured human CD34+ cells. Treatment of RPS19-deficient cells with dexamethasone restores erythroid differentiation to normal levels. We investigated the molecular basis of pharmacologic therapies for DBA using oligonucleotide microarrays to survey gene expression in CD34+ cells treated with combinations of dexamethasone, erythropoietin, stem cell factor, and interleukin-3. Dexamethasone did not alter expression of RPS19 but activated a genetic program that includes a set of key hematopoietic regulatory genes. Genes specific to erythroid progenitor cells were up-regulated by dexamethasone, while genes specific to nonerythroid lineages were down-regulated. Deficiency of RPS19 therefore blocks proliferation of immature erythroid progenitor cells, and dexamethasone activates proliferation of the same cell population through mechanisms independent of RPS19. (Blood. 2005;105:4620-4626)

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Upregulation of 5′-terminal oligopyrimidine mRNA translation upon loss of the ARF tumor suppressor

Scientific Reports ◽

10.1038/s41598-020-79379-8 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Kyle A. Cottrell ◽

Ryan C. Chiou ◽

Jason D. Weber

Keyword(s):

Protein Synthesis ◽

Tumor Cells ◽

Ribosomal Proteins ◽

Human Cancer ◽

Mrna Translation ◽

Ribosome Profiling ◽

Translational Efficiency ◽

Gene Encoding ◽

Terminal Oligopyrimidine ◽

Ribosome Export

AbstractTumor cells require nominal increases in protein synthesis in order to maintain high proliferation rates. As such, tumor cells must acquire enhanced ribosome production. How the numerous mutations in tumor cells ultimately achieve this aberrant production is largely unknown. The gene encoding ARF is the most commonly deleted gene in human cancer. ARF plays a significant role in regulating ribosomal RNA synthesis and processing, ribosome export into the cytoplasm, and global protein synthesis. Utilizing ribosome profiling, we show that ARF is a major suppressor of 5′-terminal oligopyrimidine mRNA translation. Genes with increased translational efficiency following loss of ARF include many ribosomal proteins and translation factors. Knockout of p53 largely phenocopies ARF loss, with increased protein synthesis and expression of 5′-TOP encoded proteins. The 5′-TOP regulators eIF4G1 and LARP1 are upregulated in Arf- and p53-null cells.

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Increasing adolescent girls’ social competence through cognitive counseling by social workers

Journal of Social Work ◽

10.1177/14680173211010235 ◽

2021 ◽

pp. 146801732110102

Author(s):

Chau-kiu Cheung

Keyword(s):

Social Competence ◽

Social Workers ◽

Adolescent Girls ◽

Cognitive Theory ◽

Daily Life ◽

Young Female ◽

Common Basis ◽

The Social ◽

The Common ◽

Lower Education

Summary Despite the common basis of cognitive theory for cognitive counseling and social competence development, no research has charted the effectiveness of the counseling in raising social competence in young female residents of the residential service. To examine the effectiveness, this study analyzed data gleaned from monthly surveys of young female residents and their social workers regarding the latter’s daily life cognitive counseling. The data consisted of 391 cases pairing the female residents and social workers in Hong Kong over 33 months. Findings The cases afforded a cross-lagged analysis showing the raising of the girl’s social competence by the worker’s cognitive counseling earlier in the previous month. In substantiating this raising, the analysis also indicated that earlier social competence did not affect the counseling. Applications The findings imply the worth of promoting the social worker’s daily life cognitive counseling to advance girl residents’ social competence. Such counseling is particularly helpful to girls with lower education, who are lower in social competence.

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The Common Denominator of Land Classification in Canada: an Ecological Approach to Mapping

The Forestry Chronicle ◽

10.5558/tfc56019-1 ◽

1980 ◽

Vol 56 (1) ◽

pp. 19-20 ◽

Cited By ~ 15

Author(s):

J. S. Rowe

Keyword(s):

Ecological Approach ◽

Common Denominator ◽

Land Classification ◽

Ecological Land Classification ◽

Common Basis ◽

The Common

The cores and boundaries of land units are located by reference to relationships between climate, landform and biota in ecological land classification. This appeal to relationships, rather than to climate, or to geomorphology, or to soils, or to vegetation alone, provides the common basis for land classification.

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