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1
Malaney, Prerna, Miguel Gallardo, Marisa J. Hornbaker, Xiaorui Zhang, Todd Link, Vrutant Shah, Sanzhar Alybayev, et al. "hnRNP K: A Regulator of Global Transcription and Translation That Drives Lymphomagenesis." Blood 132, Supplement 1 (November 29, 2018): 1346. http://dx.doi.org/10.1182/blood-2018-99-116163.
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Abstract hnRNP K is an RNA binding protein that controls a multitude of cellular processes and is aberrantly expressed in cancers. We have previously shown that hnRNP K functions as a haploinsufficient tumor suppressor in AML patients with 9q deletions. However, overexpression of hnRNP K is the more commonly observed clinical phenomenon. We have recently discovered that hnRNP K overexpression in patients with diffuse large B-cell lymphoma correlates with dismal outcomes and directly resulted in the development of lymphomas in transgenic mice. To understand the mechanistic basis for the oncogenicity of hnRNP K overexpression and to identify therapeutic vulnerabilities, we performed RNA-sequencing, RNA immunoprecipitation following by sequencing (RIP-Seq), mass spectrometry, and polysome assays. We observed that hnRNP K regulates both global transcription and translational processes within the cell via modulation of 7SK and translation initiation proteins (such as the eIFs and PABP), respectively. Consequently, we hypothesized that aberrant hnRNP K expression primarily perturbs oncogenes with short half-lives. Mechanistically, we identified that hnRNP K binds to the RNA and regulates the expression of a plethora of critical oncogenes and tumor suppressors involved in hematologic malignancies such as c-Myc, RUNX1, and Cyclin D1. As proof of concept for clinical applications, we have demonstrated that hnRNP K-driven c-Myc overexpression renders tumors susceptible to bromodomain inhibition. Given that hnRNP K directs global transcription and translation, it is likely that hnRNP K overexpressing tumors will also be sensitive to transcriptional and translational inhibitors such as CDK9 inhibitors and omacetaxine mepesuccinate, respectively. However, since hnRNP K also regulates a plethora of additional cellular processes that extend far beyond mRNA and protein synthesis, there is a need to develop hnRNP K-specific inhibitors that will only target these activities. Thus, we have recently begun to identify small molecule compounds that can directly inhibit hnRNP K-RNA binding function on specific targets using an in vitro fluorescent binding assay. Using this assay, we are currently screening a library of 70,000 small molecule compounds to identify agents that can prevent hnRNP K-RNA interactions. In summary, we have established that hnRNP K is a bona fide oncogene that drives lymphomagenesis. Global analyses have revealed therapeutic vulnerabilities of hnRNP K overexpressing tumors. Furthermore, using our in vitro RNA binding assays, we anticipate identification of novel hnRNP K-specific inhibitors. Disclosures No relevant conflicts of interest to declare.
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Nahar, Rahul, Parham Ramezani-Rad, Sinisa Dovat, Maike Buchner, Thomas G. Graeber, and Markus Muschen. "Mechanisms of Ikaros-Mediated Tumor Suppression." Blood 118, no. 21 (November 18, 2011): 408. http://dx.doi.org/10.1182/blood.v118.21.408.408.
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Abstract Abstract 408 Background: The Ikaros (IKZF1) tumor suppressor is deleted in >80% of the cases of Ph+ ALL. While Ikaros cooperates with pre-B cell receptor signaling to induce cell cycle exit in Ph+ ALL (Trageser et al., J Exp Med, 2009), the mechanism of Ikaros-mediated tumor suppression is poorly understood. Here we report on a series of genetic experiments that show that Ikaros (i) interferes with key survival pathways downstream of the BCR-ABL1 kinase, (ii) inhibits leukemia cell proliferation through interaction with the pre-B cell receptor signaling pathway and (iii) activates the tumor suppressors p53, p21 and p27. Results: To elucidate the mechanism of Ikaros-dependent tumor suppression in BCR-ABL1-driven B cell lineage leukemia, we studied regulation of critical phosphorylation events downstream of the BCR-ABL1 kinase as a central mediators of survival and proliferation. Reconstitution of Ikaros expression in BCR-ABL1-transformed pre-B ALL cells resulted in rapid and global dephosphorylation comparable to the effect of Imatinib. A detailed analysis showed that Ikaros-induced dephosphorylation events affect activation of Stat5 (Y694), AKT (S473), ERK1/2 (T202 and Y204) and SRC (Y416). Interestingly, both Imatinib-treatment and reconstitution of pre-B cell receptor signaling using retroviral vectors for expression of the m heavy chain or the BLNK adapter molecule have the same effects as reconstitution of Ikaros. In fact, a comprehensive gene expression analysis demonstrated that Ikaros reconstitution resulted in similar gene expression changes as reconstitution of pre-B cell receptor signaling (m heavy chain or BLNK), reconstitution of PAX5, Cre-mediated deletion of Stat5 or Myc, or treatment with Imatinib. The signature of common gene expression changes shared between reconstitution of Ikaros, Pax5, m heavy chain, BLNK and inducible deletion of Stat5 or Myc and Imatinib-treatment involves known tumor suppressors including SPIB, BTG1, and BTG2. These findings suggest that reconstitution of tumor suppressive transcription factor (Ikaros, Pax5) converges with pre-B cell receptor-mediated tumor suppression. To better understand how pre-B cell receptor signaling and Ikaros intersect, we combined reconstitution of Ikaros with genetic deletion of either the (more proximal) SYK kinase or the (more distal) BLNK adapter molecule. While inducible Cre-mediated deletion of Syk had no effect on Ikaros-mediated tumor suppression, deletion of the BLNK adapter compromised the ability of Ikaros to function as tumor suppressor. These findings were confirmed in an in vivo transplantation experiment. While mice transplanted with Ikaros+ BLNK+ leukemia cells survived indefinitely, mice transplanted with Ikaros- BLNK+, Ikaros+ BLNK- or Ikaros- BLNK- leukemia cells died after 24 to 31 days post transplantation. While these findings provide genetic evidence for collaboration between the Ikaros and pre-B cell receptor tumor suppressor pathways, Ikaros and pre-B cell receptor signaling differ with respect to activation of classical tumor suppressor pathways. While reconstitution of pre-B cell receptor signaling failed to activate Arf, p53 or p27, protein levels of all these molecules were strongly upregulated by Ikaros. In agreement with these findings, reconstitution of pre-B cell receptor signaling had the same tumor suppressive effect in wildtype leukemia cells as in Arf−/−, p53−/− as well as p27−/− leukemia cells. Conversely, deletion of Arf and p53 significantly diminished the ability of Ikaros to function as tumor suppressor. Conclusion: Ikaros deletion represents a near-obligatory lesion in the pathogenesis of Ph+ ALL. Here we provide genetic evidence for three novel pathways of Ikaros-mediated tumor suppression. Like PAX5, Ikaros reconstitution results in multiple dephosphorylation events (Stat5, AKT, ERK1/2 and SRC are affected). In collaboration with the pre-B cell receptor and its downstream adapter molecule BLNK, Ikaros suppressed MYC and inhibits cell cycle progression. Induction of the Arf/p53 pathway represents a distinct function of Ikaros, which is not shared with the pre-B cell receptor signaling pathway. Disclosures: No relevant conflicts of interest to declare.
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How, Jing Yuan, Rebecca K. Stephens, Krystle Y. B. Lim, Patrick O. Humbert, and Marc Kvansakul. "Structural basis of the human Scribble–Vangl2 association in health and disease." Biochemical Journal 478, no. 7 (April 6, 2021): 1321–32. http://dx.doi.org/10.1042/bcj20200816.
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Scribble is a critical cell polarity regulator that has been shown to work as either an oncogene or tumor suppressor in a context dependent manner, and also impacts cell migration, tissue architecture and immunity. Mutations in Scribble lead to neural tube defects in mice and humans, which has been attributed to a loss of interaction with the planar cell polarity regulator Vangl2. We show that the Scribble PDZ domains 1, 2 and 3 are able to interact with the C-terminal PDZ binding motif of Vangl2 and have now determined crystal structures of these Scribble PDZ domains bound to the Vangl2 peptide. Mapping of mammalian neural tube defect mutations reveal that mutations located distal to the canonical PDZ domain ligand binding groove can not only ablate binding to Vangl2 but also disrupt binding to multiple other signaling regulators. Our findings suggest that PDZ-associated neural tube defect mutations in Scribble may not simply act in a Vangl2 dependent manner but as broad-spectrum loss of function mutants by disrupting the global Scribble-mediated interaction network.
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Georgescu, Maria-Magdalena. "TAMI-32. TEMPOROSPATIAL INVASION AND GENETIC EVOLUTION FROM INFRATENTORIAL TO SUPRATENTORIAL COMPARTMENT IN DIFFUSE MIDLINE GLIOMA." Neuro-Oncology 22, Supplement_2 (November 2020): ii220. http://dx.doi.org/10.1093/neuonc/noaa215.920.
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Abstract Diffuse midline gliomas (DMGs) are very aggressive pediatric brain tumors with dismal prognosis due to therapy-resistant tumor growth and invasion. We performed the first integrated histologic/genomic/proteomic analysis of 21 tumor foci from three pontine DMG cases with supratentorial dissemination. Histone H3.3 K27M was the driver mutation, usually at high variant allele fraction due to recurrent chromosome 1q copy number gain, in combination with germline variants in ATM, FANCM and MYCN genes. Both previously reported and novel recurrent copy number variations and somatic pathogenic mutations in chromatin remodeling, DNA damage response and PI3K/MAPK growth pathways were variably detected, either in multiple or isolated foci. Proteomic analysis showed global upregulation of histone H3, lack of K27 tri-methylation, and further impairment of polycomb repressive complex 2 by ASXL1 downregulation. Activation of oncogenic pathways resulted from combined upregulation of N-Myc, SOX2, p65/p50 NF-kB and STAT3 transcription factors, EGFR, FGFR2, PDGFRa/b and MET receptor tyrosine kinases, and downregulation of PHLPP1/2, PTEN and p16/INK4A tumor suppressors. Upregulation of SMAD4, PAI-1, CD44, and c-Src in multiple foci most likely contributed to invasiveness. This integrated comprehensive analysis allowed spatiotemporal modeling of tumor progression and identified two general pathways of supratentorial invasion, and a multitude of migratory subpopulations within the infratentorial compartment. It also delineated common signaling pathways and potential therapeutic targets, revealing an unsuspected activation of a multitude of oncogenic pathways that may explain the resistance of DMG to current therapies.
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Ono, B. I., R. Fujimoto, Y. Ohno, N. Maeda, Y. Tsuchiya, T. Usui, and Y. Ishino-Arao. "UGA suppressors in Saccharomyces cerevisiae: allelism, action spectra and map positions." Genetics 118, no. 1 (January 1, 1988): 41–47. http://dx.doi.org/10.1093/genetics/118.1.41.
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Abstract Sixty independent UGA suppressors of Saccharomyces cerevisiae have been studied. They are dominant and are divided into 16 groups (loci) by recombination. Suppressors representing these loci are divided into two classes by action spectra; four in class 1 (a broad action spectrum) and 12 in class 2 (a narrow action spectrum). Class 1 suppressors are less frequent in terms of not only total number but also number per locus than class 2 suppressors, indicating difference in either or both mutation frequency and selective pressure between suppressors of the two classes. Two of the class 1 suppressors, SUP152 and SUP161, do not recombine with SUP28 and SUP33, leucine-inserting UAA suppressors, respectively, indicating that they are mutations in genes coding for tRNA(Leu)UUA. Of the remaining two class 1 suppressors, SUP160 which causes lethality in the psi+ cytoplasm is mapped on chromosome XV very close to the centromere, and SUP165 on the right arm of chromosome XIV 44 cM distal to lys9. Of the class 2 suppressors, ten do not recombine with one or another of previously known UGA suppressors. The remaining two class 2 suppressors, SUP154 and SUP155, are mapped on the left and right arms of chromosome VII, respectively.
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Chattopadhyay, Gopinath, Jayantika Bhowmick, Kavyashree Manjunath, Shahbaz Ahmed, Parveen Goyal, and Raghavan Varadarajan. "Mechanistic insights into global suppressors of protein folding defects." PLOS Genetics 18, no. 8 (August 29, 2022): e1010334. http://dx.doi.org/10.1371/journal.pgen.1010334.
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Most amino acid substitutions in a protein either lead to partial loss of function or are near neutral. Several studies have shown the existence of second-site mutations that can rescue defects caused by diverse loss of function mutations. Such global suppressor mutations are key drivers of protein evolution. However, the mechanisms responsible for such suppression remain poorly understood. To address this, we characterized multiple suppressor mutations both in isolation and in combination with inactive mutants. We examined six global suppressors of the bacterial toxin CcdB, the known M182T global suppressor of TEM-1 β-lactamase, the N239Y global suppressor of p53-DBD and three suppressors of the SARS-CoV-2 spike Receptor Binding Domain. When coupled to inactive mutants, they promote increased in-vivo solubilities as well as regain-of-function phenotypes. In the case of CcdB, where novel suppressors were isolated, we determined the crystal structures of three such suppressors to obtain insight into the specific molecular interactions responsible for the observed effects. While most individual suppressors result in small stability enhancements relative to wildtype, which can be combined to yield significant stability increments, thermodynamic stabilisation is neither necessary nor sufficient for suppressor action. Instead, in diverse systems, we observe that individual global suppressors greatly enhance the foldability of buried site mutants, primarily through increase in refolding rate parameters measured in vitro. In the crowded intracellular environment, mutations that slow down folding likely facilitate off-pathway aggregation. We suggest that suppressor mutations that accelerate refolding can counteract this, enhancing the yield of properly folded, functional protein in vivo.
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Gowda, Chandrika, Chunhua Song, Sadie Steffens, Yali Ding, Bo Zhang, Feng Yue, Soumya Iyer, et al. "CK2 Inhibitor CX4945 Shows Strong In Vivo Anti Leukemia Effect in AML Via Augmented Ikaros-Mediated Regulation of Global Epigenetic Landscape." Blood 134, Supplement_1 (November 13, 2019): 2522. http://dx.doi.org/10.1182/blood-2019-131200.
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Over-expression of Casein Kinase II (CK2) pro-oncogenic kinase in Acute Myelogenous Leukemia (AML) is associated with poor prognosis. Inhibition of CK2 by siRNAs or with the specific inhibitor, CX-4945, shows strong cytotoxic effects. CK2 is a ubiquitous, constitutively active serine/ threonine kinase which has been implicated in leukemia progression via multiple mechanisms. One of the well-established mechanism is CK2 mediated phosphorylation and impairment of tumor suppressor function of Ikaros transcription factor. Impaired function of Ikaros has been associated with the development of leukemia including AML. In B-cell lymphoblastic leukemia, CK2 inhibition has been shown to exert a therapeutic effect via restoration and/or enhancement of the tumor suppressor activity of the Ikaros protein. The mechanism of therapeutic action of CK2 inhibition in AML is largely unknown and in vivo efficacy CK2 inhibitors in AML has never been established. Here we report anti-leukemia effect of CX-4945 in preclinical models of AML and demonstrate mechanism of action of CK2 inhibitor via restoration of Ikaros driven global regulation of epigenetic landscape. In order to study the effect of CK2 inhibition on Ikaros function in AML, we used U937 - a human myelomonocytic leukemia cell line with high baseline CK2 expression. U937 cells were treated with specific CK2 inhibitor, CX4945 for 72 hours. CK2 activity and Ikaros phosphorylation was measured using CK2 kinase assay and in vivo labeling - radio immunoblot assay. Results showed significant decrease in CK2 activity and Ikaros phosphorylation with no change in overall expression of the Ikaros protein. Expression analysis using RNA sequencing showed that treatment with CX-4945 caused significant upregulation of genes controlling immunity, and inflammation; and downregulation of genes involved in nucleic acid metabolism, RNA processing, and translation. Analysis of global genome-wide Ikaros occupancy using Chromatin Immunoprecipitation followed by next generation sequencing (ChIP-seq) of CX4945 treated U937 cells demonstrated that CX-4945 treatment significantly increased the number of Ikaros binding sites as well as increased peak strength while minimally re-distributing Ikaros' global genomic occupancy. While increased binding to the Promoter, Gene Body, and Gene Desert elements in CX-4945-treated cells was similar, the increase in Ikaros' DNA binding to enhancers was particularly pronounced. Further analysis showed that enhanced Ikaros DNA binding following treatment with CX-4945, directly induces formation of de novo enhancers. In order to test whether enhanced DNA binding of Ikaros is accompanied by augmented Ikaros function in the global epigenetic regulation of gene expression. We determined and compared chromatin accessibility of U937 cells before and after treatment with CX-4945, using ATAC-seq. Results indicate that Ikaros-induced de novo open chromatin at distal regulatory regions controls genes involved in the negative regulation of biological processes and cellular metabolism. Overall, these data demonstrate that, augmented Ikaros DNA-binding following CK2 inhibition resulted in 1) Ikaros' pioneering activity, 2) Ikaros' ability to induce the de novo formation of enhancers and super-enhancers, and 3) Ikaros' ability to induce the de novo formation of active enhancers and to activate poised enhancers. Together, these data uncover novel Ikaros functions in regulating the epigenetic landscape and identifies CK2 as a critical regulator of Ikaros activity. Next, we treated AML xenograft model of luciferase labelled U937 cells with CX4945 via oral gavage at dose 200mg/kg/day for 3 weeks and demonstrated significantly lower leukemia burden in treated group as measured by decreased bio-luminescence imaging. In summary, these results demonstrate for the first time that CK2 inhibitor, CX-4945 has strong anti-leukemia effect in AML preclinical models. One of the mechanisms by which CX4945 exert a therapeutic effect in AML involves enhancing Ikaros' function as regulator of global epigenomic landscape. These results provide strong mechanistic basis to develop novel targeted combination therapies using CK2 inhibitors for treatment of AML. Further studies evaluating combination therapies using patient derived xenograft (PDX) models of AML are underway. Disclosures Payne: Elf Zone, Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.
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Scholl, Amanda, Alexander Muselman, and Dong-Er Zhang. "An Intronic Suppressor Element Regulates RUNX1 Alternative Polyadenylation." Blood 126, no. 23 (December 3, 2015): 3578. http://dx.doi.org/10.1182/blood.v126.23.3578.3578.
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Abstract Polyadenylation is a post-transcriptional modification where the 3' end of an mRNA is cleaved and 250-300 adenines are added. It is predicted that 70-75% of human genes have more than one polyadenylation sequence (PAS) and are subject to alternative polyadenylation (APA). APA events affect the coding sequence of a gene when a proximal PAS is located within an intron, constitutive exon, or alternative exon. Gene expression is also affected if there are multiple PAS within the distal 3' untranslated region (UTR); proximal PAS usage shortens the 3'UTR, which can remove cis-regulatory regions such as miRNA and RNA-binding protein (RBP) sites. Furthermore, global changes in APA are linked to cellular state-proximal PAS usage is associated with immature developmental phases, cell proliferation, and cancerous phenotypes. Consequently, APA is a pertinent post-transcriptional modification that regulates gene expression and isoform generation across developmental stages and tissue types. Despite its significance, there are few APA studies in the hematology field, and those that exist have focused on global shifts in PAS usage. In this study, we uniquely focus on the APA mechanism of a single gene, RUNX1, and how this event can alter hematopoietic stem cell (HSC) homeostasis and hematopoiesis. There are three main isoforms of RUNX1 that differ in promoter and/or PAS usage. RUNX1b/c use different promoters, but have identical C-terminal regions. RUNX1a utilizes the same promoter as RUNX1b, but differs from both RUNX1b/c due to usage of a proximal PAS located in alternative exon 7a. RUNX1b/c are robustly expressed in most progenitor populations and differentiated blood cell lineages, whereas RUNX1a is restricted to human CD34+ HSCs. Functionally, RUNX1b/c promote HSC differentiation and lineage commitment, whereas RUNX1a expands HSCs and their engraftment potential, a property with therapeutic advantages but leukemic potential. Due to the difference in expression pattern and distinct functionality of RUNX1a compared to RUNX1b/c, it is relevant to study the APA event that dictates isoform generation. Elucidating this mechanism could provide valuable insight into the transient control of the HSC population for therapeutic benefit and illuminate new leukemogenic pathways. To study RUNX1 APA, we cloned alternative terminal exon 7a (RUNX1a) and constitutive exon 7b (RUNX1b/c) in between the two exons of a split GFP minigene reporter, along with 500 bp of their upstream and downstream flanking introns. We hypothesized that exon 7a would be skipped during processing of the minigene construct because the proximal PAS is rarely used in vivo. Conversely, exon 7b, the penultimate exon in RUNX1b/c, would be spliced in between the GFP exons, disrupting the GFP protein. These constructs were tested in KG-1a and U937 cells. Flow cytometry for GFP fluorescence supported our hypothesis as the exon 7a minigene produced a robust GFP signal and the exon 7b minigene produced no GFP signal. We confirmed that the GFP changes were due to the hypothesized mRNA processing events by performing RT-PCR using primers specific to the two GFP exons. These data show that important cis-regulatory elements that determine RUNX1 APA are located within exon 7a, 7b, and the cloned intronic regions. Next, we altered these minigenes by strategically making chimeric constructs that consist of either exon 7a or 7b with all combinations of upstream/downstream flanking introns. We discovered that replacing the intron upstream of exon 7a confers 2-5 fold greater splicing and polyadenylation of exon 7a, indicative of RUNX1a isoform generation. Therefore, a suppressor cis-element is located in this upstream intronic region. However, placing this intron upstream of exon 7b is not sufficient to reduce its inclusion between the GFP exons. Instead, both the upstream and downstream intronic regions flanking exon 7a are required. This suggests an RNA-looping mechanism that prevents splicing and usage of the exon 7a proximal PAS. Cleavage factor (CFIm) and Polypyrimidine-tract binding protein 1 (PTBP1) are RBPs involved in splicing and polyadenylation that alter mRNA processing by RNA-looping. We aim to narrow down the suppressor region upstream of exon 7a to identify a consensus sequence and the respective RBP that diminishes RUNX1 proximal PAS usage. This knowledge can be leveraged to enhance RUNX1a production and expand HSCs for therapeutic benefit. Disclosures No relevant conflicts of interest to declare.
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Maine, E. M., and J. Kimble. "Suppressors of glp-1, a gene required for cell communication during development in Caenorhabditis elegans, define a set of interacting genes." Genetics 135, no. 4 (December 1, 1993): 1011–22. http://dx.doi.org/10.1093/genetics/135.4.1011.
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Abstract The glp-1 gene is essential for two cell interactions that control cell fate in Caenorhabditis elegans: induction of anterior pharynx in the embryo and induction of mitotic proliferation in the germ line. To identify other genes involved in these cell interactions, we have isolated suppressors of two temperature sensitive alleles of glp-1. Each of 14 recessive suppressors rescues both embryonic and germline glp-1(ts) defects. These suppressors are extragenic and define a set of six genes designated sog, for suppressor of glp-1. Suppression of glp-1 is the only obvious phenotype associated with sog mutations. Mutations in different sog genes show allele-specific intergenic noncomplementation, suggesting that the sog gene products may interact. In addition, we have analyzed a semidominant mutation that suppresses only the glp-1 germline phenotype and has a conditional feminized phenotype of its own. None of the suppressors rescues a glp-1 null mutation and therefore they do not bypass a requirement for glp-1. Distal tip cell function remains necessary for germline proliferation in suppressed animals. These suppressor mutations identify genes that may encode other components of the glp-1 mediated cell-signaling pathway or regulate glp-1 expression.
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Lissemore, J. L., P. D. Currie, C. M. Turk, and E. M. Maine. "Intragenic dominant suppressors of glp-1, a gene essential for cell-signaling in Caenorhabditis elegans, support a role for cdc10/SWI6/ankyrin motifs in GLP-1 function." Genetics 135, no. 4 (December 1, 1993): 1023–34. http://dx.doi.org/10.1093/genetics/135.4.1023.
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Abstract The glp-1 gene product mediates cell-cell interactions required for cell fate specification during development in Caenorhabditis elegans. To identify genes that interact with glp-1, we screened for dominant suppressors of two temperature-sensitive glp-1 alleles and recovered 18 mutations that suppress both germline and embryonic glp-1 phenotypes. These dominant suppressors are tightly linked to glp-1 and do not bypass the requirement for a distal tip cell, which is thought to be the source of a signal that is received and transduced by the GLP-1 protein. Using single-strand conformation polymorphism (SSCP) analysis and DNA sequencing, we found that at least 17 suppressors are second-site intragenic revertants. The suppressors, like the original glp-1(ts) mutations, are all located in the cdc10/SWI6/ankyrin domain of GLP-1. cdc10/SWI6/ankyrin motifs have been shown to mediate specific protein-protein interactions in other polypeptides. We propose that the glp-1(ts) mutations disrupt contact between GLP-1 and an as yet unidentified target protein(s) and that the dominant suppressor mutations restore appropriate protein-protein interactions.
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Kapatai, Georgia, Stephen O. Nyangoma, Hannah M. Martin, and Pamela R. Kearns. "DNA Methylation in Resistant Paediatric Acute Lymphoblastic Leukaemia." Blood 112, no. 11 (November 16, 2008): 1185. http://dx.doi.org/10.1182/blood.v112.11.1185.1185.
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Abstract Aberrant DNA methylation is a frequent phenomenon in paediatric acute lymphoblastic leukaemia (ALL). Increased methylation has been identified as an independent factor of poor prognosis in paediatric ALL patients. This study investigates the evolution of epigenetic changes in resistant and relapsed paediatric ALL to increase our understanding of the mechanisms of treatment failure in these patients. The primary objective is to establish global DNA methylation profile in ALL and whether changes in this profile are associated with chemo-resistance and relapse. We performed a genome-wide analysis of CpG island methylation in leukaemic blasts on a cohort of 22 paediatric ALL patients; 11 at presentation and 11 at relapse. Global methylation profiles were investigated using the recently developed CpG island array technology, which includes 12,192 sequenced CpG-island clones obtained from the Wellcome Trust Sanger Institute (Cambridge, UK). These clones have undergone comprehensive sequence analysis which validated the array content and confirmed that 80% of the clones have usable sequences that can be aligned to genomic DNA. The majority of CpG-island loci are localised to known distal promoter regions or close to a transcriptional start site. We have validated the application of this technology to leukaemia cells using established ALL and AML cell lines. Pairwise Pearson correlation coefficient, used to compare log2 ratios between triplicate experiments, revealed high correlation values between replicates (median=0.85), demonstrating significant reproducibility. Bisulphite sequencing was performed to confirm that this technology could reliably depict the actual methylation status of the CpG islands. We have evaluated CpG island methylation profiling in childhood ALL both at presentation and relapse. We report that ALL specific CpG island methylation patterns are emerging. We have identified a significant number of genes, involved in cell growth and differentiation and cell cycle regulation that are consistently differentially methylated between paediatric ALL patients and healthy controls. Expressly, a number of Hox genes and Hox-genes regulators, involved in cell differentiation are differentially methylated in leukaemic blasts compared to controls. Comparisons between methylation profiles at presentation and relapse demonstrate that overall genes that are methylated at presentation remain methylated in relapse; however there is an important subset of genes that become differentially methylated. At relapse, there is a significant increase in methylation levels of a set of pro-apoptotic and tumour suppressor genes, as well as several genes involved in drug metabolism. Interestingly, a group of genes involved in ErbB signalling pathway are differentially methylated in relapse, suggesting that epigenetic regulation of this pathway might be implicated in resistant disease. Our results suggest altered methylation status within a defined subset of genes may be implicated in relapse of ALL.
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Moldal, Torfinn, Aksel Bernhoft, Grethe Rosenlund, Magne Kaldhusdal, and Erling Koppang. "Dietary Deoxynivalenol (DON) May Impair the Epithelial Barrier and Modulate the Cytokine Signaling in the Intestine of Atlantic Salmon (Salmo salar)." Toxins 10, no. 9 (September 14, 2018): 376. http://dx.doi.org/10.3390/toxins10090376.
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Impaired growth, immunity, and intestinal barrier in mammals, poultry, and carp have been attributed to the mycotoxin deoxynivalenol (DON). The increased use of plant ingredients in aquaculture feed implies a risk for contamination with mycotoxins. The effects of dietary DON were explored in 12-month-old Atlantic salmon (Salmo salar) (start weight of 58 g) that were offered a standard feed with non-detectable levels of mycotoxins (control group) or 5.5 mg DON/kg feed (DON group). Each group comprised two tanks with 25 fish per tank. Five fish from each tank were sampled eight weeks after the start of the feeding trial, when mean weights for the control and DON groups were 123.2 g and 80.2 g, respectively. The relative expression of markers for three tight junction proteins (claudin 25b, occludin, and tricellulin) were lower, whereas the relative expression of a marker for proliferating cell nuclear antigen was higher in both the mid-intestine and the distal intestine in fish fed DON compared with fish from the control group. The relative expression of markers for two suppressors of cytokine signaling (SOCS1 and SOCS2) were higher in the distal intestine in fish fed DON. There was no indication of inflammation attributed to the feed in any intestinal segments. Our findings suggest that dietary DON impaired the intestinal integrity, while an inflammatory response appeared to be mitigated by suppressors of cytokine signaling. A dysfunctional intestinal barrier may have contributed to the impaired production performance observed in the DON group.
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Samur, Mehmet K., Irtisha Singh, Lee Shih-Han, Adam Samuel Sperling, Mariateresa Fulciniti, Yu-Tzu Tai, Giovanni Parmigiani, Christina S. Leslie, Christine Mayr, and Nikhil C. Munshi. "3' Untranslated Region (UTR) Alterations Are Frequently Targeted By MM-Related Mirnas and Affects the Clinical Outcome." Blood 128, no. 22 (December 2, 2016): 4447. http://dx.doi.org/10.1182/blood.v128.22.4447.4447.
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Abstract More than half of human genes use alternative cleavage and polyadenylation to generate alternative 3' untranslated region (3'UTR) isoforms that play a role in gene expression regulation. The 3' untranslated region (3'UTR) of mRNA contains elements that play regulatory roles in polyadenylation, localization, translation efficiency, and mRNA stability. Although relative contributions of different regulatory mechanisms remain poorly understood, several recent studies showed that alterations in 3'UTRs might affect protein localization as well as their interactions with other proteins. Here, we obtained global measurements of 3' UTR sequencing and RNA-seq in MM and normal plasma cells to study the effects of 3'UTR alterations in MM. Whole transcriptome sequencing (RNAseq) data from 420 uniformly treated newly diagnosed MM samples were compared with 18 normal plasma cell by using dynamic analyses of alternative PolyAdenylation and results were compared with alternative 3'UTR isoforms measured using 3'-seq, an established quantitative 3' end sequencing method from 15 samples pilot study. We observed ~10000 different isoforms with a median frequency of 297 (range 1-2495) altered 3'UTRs per sample. We observed 563 isoforms that have distal alternative poly A (APA) site and 449 isoforms that have proximal APA site compared to normal plasma cells in at least 10% of our patients. Enrichment analysis showed that short UTR genes are significantly targeted by miR-506, miR-133, miR-130, miR-27, miR-181 and miR-200 (FDR q-value < 0.05). We also observed that expression of 90 genes significantly increased between those samples with shorter UTR vs. regular UTR. Longer UTR genes are enriched in mir-124, mir-186, mir-200, mir-302, mir-495 and expression of 123 genes were significantly downregulated between long UTR and others. There were no tumor suppressor genes and 8 oncogenes in short UTR genes and 4 tumor suppressor and 14 oncogenes in longer UTR genes. Our results were confirmed using the 3'seq study which showed that 170 genes have longer UTR in MM compared to normal plasma cells and 187 genes have shorter UTR. ~60% of longer and ~65% of shorter UTR genes reported by 3'seq were also observed with RNAseq. Furthermore, we focused on common genes reported by both high-throughput sequencing methods and analyzed any connection between outcome and UTR shortening or lengthening. We observed 26 genes with altered UTR regions have impact on PFS or OS. In conclusion, we report significant alternate UTR usage, including intronic UTRs in MM affecting the disease biology and clinical outcome. Our data suggests the need to further investigate the molecular impact of alternate UTR usage and its relationship with miR in myeloma. Disclosures No relevant conflicts of interest to declare.
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Yang, Liubin, Benjamin Rodriguez, Min Luo, Mira Jeong, David Ruau, Choladda V. Curry, Xiaotian Zhang, et al. "Dnmt3a-Deletion Accelerates FLT3-ITD Malignancies In Mice By Hypomethylation Of Enhancer Sites and Activating Stem Cell Programs; Implications For Therapy." Blood 122, no. 21 (November 15, 2013): 595. http://dx.doi.org/10.1182/blood.v122.21.595.595.
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Abstract The de novo DNA methyltransferase (DNMT) 3A is mutated in 50% of patients with mixed phenotype acute leukemia, 20% with acute myeloid leukemia (AML) and 18% with T-cell acute lymphoblastic leukemia (T-ALL). The mechanisms through which mutant DNMT3A contributes to hematologic malignancy are poorly understood. In mice, deletion of Dnmt3a in hematopoietic stem cells (HSCs) leads to abnormal DNA methylation and inhibition of differentiation, but is insufficient for leukemic transformation. To study the role of Dnmt3a in leukemia, we combined Dnmt3a-deletion with the activated FLT3 proto-oncogene (FLT3-ITD), a frequent co-mutation with DNMT3A in AML patients, to establish a murine model of Dnmt3a-associated malignancy. In mice transplanted with Dnmt3a-knockout (KO) or wild-type (WT) bone marrow cells transduced with a FLT3-ITD retrovirus, Dnmt3a-loss dramatically impacted the disease phenotype. Dnmt3aKO/ITD transplanted mice had significantly shortened survival (79 days vs. 116 days) and increased rate of acute leukemia compared to mice with ITD alone. The mice developed CD4+CD8+ Notch activation-associated T-ALL or myeloproliferative disease (MPD), or concurrently both, consistent with previous studies of FLT3-ITD in mice. To determine the leukemia-initiating population, we transplanted sorted HSC, myeloid, and lymphoid progenitors transduced with FLT3-ITD. All mice transplanted with HSC and myeloid progenitors succumbed to both malignancies. To uncover the mechanisms by which Dnmt3a-deletion accelerated acute leukemia, we analyzed changes in DNA methylation in T-ALL blasts by whole genome bisulfite sequencing. Compared to Dnmt3aWT/ITD, Dnmt3aKO/ITD blasts exhibited global hypomethylation, particularly at distal enhancer sites. These hypomethylated enhancer sites were associated with genes in signaling pathways, transcription regulators, and metabolic pathways in cancer (KEGG and GO Analysis). Transcriptome analysis showed that relative to Dnmt3aWT/ITD, the Dnmt3aKO/ITD blasts had 1577 significantly differentially expressed genes positively related to cancer, cellular growth, and proliferation, and negatively to apoptosis by Ingenuity Pathway Analysis (IPA). Surprisingly, we observed increased expression of genes related to HSCs and myeloid function and decreased expression of genes related to lymphocyte function. Human AML signature genes (Oncomine) were also upregulated in our mouse model. Predicted activated pathways include Myc, Nfe2l2, Eif4e, E2f1, Csf2, Cebpb, Vegf, Rxra, Ezh2, and Brd4 and inhibited pathways include tumor suppressors Rb, let7, Cdkn2a, and Tob1 (IPA). We did not observe changes in genomic copy number variation by chromosomal comparative hybridization (cCGH). To test whether Dnmt3a-deletion could functionally bestow stem cell properties on pre-leukemic cells, we examined self-renewal capabilities of malignant cells of Flt3+/ITD knock-in mouse (an ITD mutation knocked in to the endogenous murine Flt3 allele causing MPD). Remarkably, when Dnmt3aKO; Flt3+/ITD bone marrow cells were serially transplanted, MPD was seen in all recipients, compared to none in Dnmt3aWT; Flt3+/ITD transplanted mice (n=7). Further, we transplanted sorted CLP, CMP, GMP, MPP, ST-HSC, LT-HSC populations and observed myeloproliferation in transplanted non-stem (CMP, GMP, ST-HSC) and stem cell (LT-HSC) populations. This strongly suggests that Dnmt3aKO synergized with Flt3-ITD to confer stem cell self-renewal abilities to transformed progenitor and stem cells. Increasingly, decitabine is being used to treat patients with AML and MDS, but whether patients with DNMT3A mutations could benefit is unclear, so we examined the impact of decitabine treatment on the retroviral transduced Dnmt3aKO/ITD mice. Monthly treatment led to significantly increased survival of Dnmt3aKO/ITD mice from T-ALL and MPD and reduced presence of ITD-transduced KO cells. Together, we demonstrate that Dnmt3aKO accelerated malignancies induced by FLT3-ITD in mouse and may shed light on how DNMT3A mutations contribute to lymphoid and myeloid disease in patients. Dnmt3a deletion ignited multilineage and stem cell programs at the expense of lymphoid programs to accelerate disease, but was extinguishable by decitabine therapy. The findings from our mouse model can be used for the development and testing of targeted epigenetic therapy for DNMT3A-associated malignancies. Disclosures: No relevant conflicts of interest to declare.
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Talbert, P. B., C. D. LeCiel, and S. Henikoff. "Modification of the Drosophila heterochromatic mutation brownDominant by linkage alterations." Genetics 136, no. 2 (February 1, 1994): 559–71. http://dx.doi.org/10.1093/genetics/136.2.559.
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Abstract The variegating mutation brownDominant (bwD) of Drosophila melanogaster is associated with an insertion of heterochromatin into chromosome arm 2R at 59E, the site of the bw gene. Mutagenesis produced 150 dominant suppressors of bwD variegation. These fall into two classes: unlinked suppressors, which also suppress other variegating mutations; and linked chromosome rearrangements, which suppress only bwD. Some rearrangements are broken at 59E, and so might directly interfere with variegation caused by the heterochromatic insertion at that site. However, most rearrangements are translocations broken proximal to bw within the 52D-57D region of 2R. Translocation breakpoints on the X chromosome are scattered throughout the X euchromatin, while those on chromosome 3 are confined to the tips. This suggests that a special property of the X chromosome suppresses bwD variegation, as does a distal autosomal location. Conversely, two enhancers of bwD are caused by translocations from the same part of 2R to proximal heterochromatin, bringing the bwD heterochromatic insertion close to the chromocenter with which it strongly associates. These results support the notion that heterochromatin formation at a genetic locus depends on its location within the nucleus.
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Shortle, David, and Beth Lin. "GENETIC ANALYSIS OF STAPHYLOCOCCAL NUCLEASE: IDENTIFICATION OF THREE INTRAGENIC "GLOBAL" SUPPRESSORS OF NUCLEASE-MINUS MUTATIONS." Genetics 110, no. 4 (August 1, 1985): 539–55. http://dx.doi.org/10.1093/genetics/110.4.539.
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ABSTRACT A collection of 77 unique missense mutations distributed across the gene encoding staphylococcal nuclease (nuc) has been assembled. These mutations were induced by random gap misrepair mutagenesis of the cloned gene and were identified in E. coli transformants expressing reduced levels of nuclease activity. Four nuc - mutations which alter amino acid residues at positions outside of the active site region of the enzyme were submitted to a second round of mutagenesis, and characterization of several independent NUC+ isolates lead to the identification of three second-site suppressor mutations within the protein-coding sequence of the nuc gene. On separation from the mutation originally suppressed and recombination with a number of other nuc - mutations, all three suppressors displayed the property of "global" suppression, i.e., phenotypic suppression of the nuclease-minus character of multiple different alleles. A simple and generally applicable strategy was used to obtain efficient homologous recombination between plasmids for purposes of mapping nuc - mutations, mapping second-site suppressors and constructing double mutant combinations from pairs of single mutations.
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Tietz, Kiel T., Braedan M. McClukey, Sarah A. Munro, Conor R. Miller, and Scott M. Dehm. "Abstract A022: Alternative polyadenylation as a therapeutic vulnerability in prostate cancer." Cancer Research 83, no. 11_Supplement (June 2, 2023): A022. http://dx.doi.org/10.1158/1538-7445.prca2023-a022.
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Abstract Prostate cancer is the second leading cause of male cancer death in the United States. While localized disease can be cured by radiation or surgery, metastatic prostate cancer presents a clinical challenge. Metastatic prostate cancer can initially be controlled by endocrine therapies that target the androgen receptor (AR), however, these tumors will inevitably develop resistance. This stage of the disease, termed castration-resistant prostate cancer (CRPC), is responsible for the majority of prostate cancer-specific deaths. Current treatment options for CRPC patients are not curable and highlight the need to develop novel therapeutic options that will more effectively treat the disease. Spliced mRNA molecules undergo cleavage and polyadenylation ~25 base pair downstream from a canonical 5’AAUAAA poly(A) site located within the 3’ untranslated region (UTR). Shortening of mRNA 3’UTRs through alternative polyadenylation has been found in numerous cancers leading to downregulation of tumor suppressor genes and upregulation of oncogenes. To investigate the function of alternative polyadenylation in CRPC, we conducted a loss-of-function screen of mRNA polyadenylation factors in hormone-sensitive LNCaP cells and hormone-insensitive LNCaP95 and 22Rv1 cells. We found that knockdown of the cleavage and polyadenylation specificity factor (CPSF) component, CPSF1, inhibited growth of all cell lines. To define pathways that are regulated by CPSF1 in prostate cancer, we identified CPSF1-dependent gene expression using RNA-seq and CPSF1-dependent poly(A) sites using poly(A)-ClickSeq (PAC-Seq). Gene set enrichment analysis of RNA-seq data revealed the Glycolysis Hallmark and Hypoxia Hallmark gene sets were positively regulated by CPSF1. Analysis of PAC-seq data revealed global induction of poly(A) sites distal to 3’ UTRs upon CPSF1 knockdown. By integrating these RNA-seq and PAC-seq datasets, we have identified AR-independent pathways that may be attractive for therapeutic targeting in prostate cancer. This study has revealed post-transcriptional gene regulation by CPSF1 as an important pathway used in CRPC. Citation Format: Kiel T. Tietz, Braedan M. McClukey, Sarah A. Munro, Conor R. Miller, Scott M. Dehm. Alternative polyadenylation as a therapeutic vulnerability in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A022.
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Käfer, Etta. "MMS Sensitivity of All Amino Acid-Requiring Mutants in Aspergillus and Its Suppression by Mutations in a Single Gene." Genetics 115, no. 4 (April 1, 1987): 671–76. http://dx.doi.org/10.1093/genetics/115.4.671.
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ABSTRACT All available amino acid-requiring mutants of Aspergillus nidulans were found to be hypersensitive to MMS (methyl methanesulfonate) to various degrees. On MMS media, secondary mutations could be selected which suppress this MMS sensitivity but do not affect the requirement. Many such mutations were analyzed and found to be alleles of one gene, smsA (=suppressor of MMS sensitivity), which mapped distal on the right arm of chromosome V. This gene is more likely to be involved in general regulation of amino acid biosynthesis than MMS uptake, since a variety of pathway interactions were clearly modified by smsA suppressors in the absence of MMS.
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Teixeira, Ruan M., Marco Aurélio Ferreira, Gabriel A. S. Raimundo, and Elizabeth P. B. Fontes. "Geminiviral Triggers and Suppressors of Plant Antiviral Immunity." Microorganisms 9, no. 4 (April 8, 2021): 775. http://dx.doi.org/10.3390/microorganisms9040775.
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Geminiviruses are circular single-stranded DNA plant viruses encapsidated into geminate virion particles, which infect many crops and vegetables and, hence, represent significant agricultural constraints worldwide. To maintain their broad-range host spectrum and establish productive infection, the geminiviruses must circumvent a potent plant antiviral immune system, which consists of a multilayered perception system represented by RNA interference sensors and effectors, pattern recognition receptors (PRR), and resistance (R) proteins. This recognition system leads to the activation of conserved defense responses that protect plants against different co-existing viral and nonviral pathogens in nature. Furthermore, a specific antiviral cell surface receptor signaling is activated at the onset of geminivirus infection to suppress global translation. This review highlighted these layers of virus perception and host defenses and the mechanisms developed by geminiviruses to overcome the plant antiviral immunity mechanisms.
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Soparkar, Ketaki, Alfred D. Kinana, Jon W. Weeks, Keith D. Morrison, Hiroshi Nikaido, and Rajeev Misra. "Reversal of the Drug Binding Pocket Defects of the AcrB Multidrug Efflux Pump Protein of Escherichia coli." Journal of Bacteriology 197, no. 20 (August 3, 2015): 3255–64. http://dx.doi.org/10.1128/jb.00547-15.
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ABSTRACTThe AcrB protein ofEscherichia coli, together with TolC and AcrA, forms a contiguous envelope conduit for the capture and extrusion of diverse antibiotics and cellular metabolites. In this study, we sought to expand our knowledge of AcrB by conducting genetic and functional analyses. We began with an AcrB mutant bearing an F610A substitution in the drug binding pocket and obtained second-site substitutions that overcame the antibiotic hypersusceptibility phenotype conferred by the F610A mutation. Five of the seven unique single amino acid substitutions—Y49S, V127A, V127G, D153E, and G288C—mapped in the periplasmic porter domain of AcrB, with the D153E and G288C mutations mapping near and at the distal drug binding pocket, respectively. The other two substitutions—F453C and L486W—were mapped to transmembrane (TM) helices 5 and 6, respectively. The nitrocefin efflux kinetics data suggested that all periplasmic suppressors significantly restored nitrocefin binding affinity impaired by the F610A mutation. Surprisingly, despite increasing MICs of tested antibiotics and the efflux ofN-phenyl-1-naphthylamine, the TM suppressors did not improve the nitrocefin efflux kinetics. These data suggest that the periplasmic substitutions act by influencing drug binding affinities for the distal binding pocket, whereas the TM substitutions may indirectly affect the conformational dynamics of the drug binding domain.IMPORTANCEThe AcrB protein and its homologues confer multidrug resistance in many important human bacterial pathogens. A greater understanding of how these efflux pump proteins function will lead to the development of effective inhibitors against them. The research presented in this paper investigates drug binding pocket mutants of AcrB through the isolation and characterization of intragenic suppressor mutations that overcome the drug susceptibility phenotype of mutations affecting the drug binding pocket. The data reveal a remarkable structure-function plasticity of the AcrB protein pertaining to its drug efflux activity.
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Winkler, Marisa L., and Robert A. Bonomo. "SHV-129: A Gateway to Global Suppressors in the SHV β-Lactamase Family?" Molecular Biology and Evolution 33, no. 2 (November 3, 2015): 429–41. http://dx.doi.org/10.1093/molbev/msv235.
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Imanishi, Ayaka, Yuma Aoki, Masaki Kakehi, Shunsuke Mori, Tomomi Takano, Yukihiko Kubota, Hon-Song Kim, Yukimasa Shibata, and Kiyoji Nishiwaki. "Genetic interactions among ADAMTS metalloproteases and basement membrane molecules in cell migration in Caenorhabditis elegans." PLOS ONE 15, no. 12 (December 2, 2020): e0240571. http://dx.doi.org/10.1371/journal.pone.0240571.
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During development of the Caenorhabditis elegans gonad, the gonadal leader cells, called distal tip cells (DTCs), migrate in a U-shaped pattern to form the U-shaped gonad arms. The ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) family metalloproteases MIG-17 and GON-1 are required for correct DTC migration. Mutations in mig-17 result in misshapen gonads due to the misdirected DTC migration, and mutations in gon-1 result in shortened and swollen gonads due to the premature termination of DTC migration. Although the phenotypes shown by mig-17 and gon-1 mutants are very different from one another, mutations that result in amino acid substitutions in the same basement membrane protein genes, emb-9/collagen IV a1, let-2/collagen IV a2 and fbl-1/fibulin-1, were identified as genetic suppressors of mig-17 and gon-1 mutants. To understand the roles shared by these two proteases, we examined the effects of the mig-17 suppressors on gon-1 and the effects of the gon-1 suppressors and enhancers on mig-17 gonadal defects. Some of the emb-9, let-2 and fbl-1 mutations suppressed both mig-17 and gon-1, whereas others acted only on mig-17 or gon-1. These results suggest that mig-17 and gon-1 have their specific functions as well as functions commonly shared between them for gonad formation. The levels of collagen IV accumulation in the DTC basement membrane were significantly higher in the gon-1 mutants as compared with wild type and were reduced to the wild-type levels when combined with suppressor mutations, but not with enhancer mutations, suggesting that the ability to reduce collagen IV levels is important for gon-1 suppression.
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Pekow, Joel, Katherine Meckel, Urszula Dougherty, Fatma Butun, Reba Mustafi, John Lim, Charis Crofton, Xindi Chen, Loren Joseph, and Marc Bissonnette. "Tumor suppressors miR-143 and miR-145 and predicted target proteins API5, ERK5, K-RAS, and IRS-1 are differentially expressed in proximal and distal colon." American Journal of Physiology-Gastrointestinal and Liver Physiology 308, no. 3 (February 1, 2015): G179—G187. http://dx.doi.org/10.1152/ajpgi.00208.2014.
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The colon differs regionally in local luminal environment, excretory function, and gene expression. Polycistronic microRNA (miR)-143 and miR-145 are downregulated early in colon cancer. We asked if these microRNAs (miRNAs) might be differentially expressed in the proximal vs. the distal colon, contributing to regional differences in protein expression. Primary transcripts and mature miR-143 and miR-145 were quantified by real-time PCR, putative targets were measured by Western blotting, and DNA methylation was assessed by sequencing bisulfite-treated DNA in proximal and distal normal colonic mucosa as well as colon cancers. Putative targets of these miRNAs were assessed following transfection with miR-143 or miR-145. Mean expression of mature miR-143 and miR-145 was 2.0-fold ( P < 0.001) and 1.8-fold ( P = 0.03) higher, respectively, in proximal than distal colon. DNA methylation or primary transcript expression of these miRNAs did not differ by location. In agreement with increased expression of miR-143 and miR-145 in proximal colon, predicted targets of these miRNAs, apoptosis inhibitor 5 (API5), ERK5, K-RAS, and insulin receptor substrate 1 (IRS-1), which are cell cycle and survival regulators, were expressed at a lower level in proximal than distal colon. Transfection of HCA-7 colon cancer cells with miR-145 downregulated IRS-1, and transfection of HT-29 colon cancer cells with miR-143 decreased K-RAS and ERK5 expression. In conclusion, miR-143 and miR-145 and the predicted target proteins API5, ERK5, K-RAS, and IRS-1 display regional differences in expression in the colon. We speculate that differences in these tumor suppressors might contribute to regional differences in normal colonic gene expression and modulate site-specific differences in malignant predisposition.
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Augustus, Anne Marie, Teresa Celaya, Fasahath Husain, Matthew Humbard, and Rajeev Misra. "Antibiotic-Sensitive TolC Mutants and Their Suppressors." Journal of Bacteriology 186, no. 6 (March 15, 2004): 1851–60. http://dx.doi.org/10.1128/jb.186.6.1851-1860.2004.
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ABSTRACT The TolC protein of Escherichia coli, through its interaction with AcrA and AcrB, is thought to form a continuous protein channel that expels inhibitors from the cell. Consequently, tolC null mutations display a hypersensitive phenotype. Here we report the isolation and characterization of tolC missense mutations that direct the synthesis of mutant TolC proteins partially disabled in their efflux role. All alterations, consisting of single amino acid substitutions, were localized within the periplasmic α-helical domain. In two mutants carrying an I106N or S350F substitution, the hypersensitivity phenotype may be in part due to aberrant TolC assembly. However, two other alterations, R367H and R390C, disrupted efflux function by affecting interactions among the helices surrounding TolC's periplasmic tunnel. Curiously, these two TolC mutants were sensitive to a large antibiotic, vancomycin, and exhibited a Dex+ phenotype. These novel phenotypes of TolCR367H and TolCR390C were likely the result of a general influx of molecules through a constitutively open tunnel aperture, which normally widens only when TolC interacts with other proteins during substrate translocation. An intragenic suppressor alteration (T140A) was isolated from antibiotic-resistant revertants of the hypersensitive TolCR367H mutant. T140A also reversed, either fully (R390C) or partially (I106N and S350F), the hypersensitivity phenotype of other TolC mutants. Our data suggest that this global suppressor phenotype of T140A is the result of impeded antibiotic influx caused by tapering of the tunnel passage rather than by correcting individual mutational defects. Two extragenic suppressors of TolCR367H, mapping in the regulatory region of acrAB, uncoupled the AcrR-mediated repression of the acrAB genes. The resulting overexpression of AcrAB reduced the hypersensitivity phenotype of all the TolC mutants. Similar results were obtained when the chromosomal acrR gene was deleted or the acrAB genes were expressed from a plasmid. Unlike the case for the intragenic suppressor T140A, the overexpression of AcrAB diminished hypersensitivity towards only erythromycin and novobiocin, which are substrates of the TolC-AcrAB efflux pump, but not towards vancomycin, which is not a substrate of this pump. This showed that the two types of suppressors produced their effects by fundamentally different means, as the intragenic suppressor decreased the general influx while extragenic suppressors increased the efflux of TolC-AcrAB pump-specific antibiotics.
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Adams, Donovan, Victoria M. Swenson, and G. Richard Scott. "Global Distribution of Marginal Accessory Tubercles of the Maxillary Premolars." Dental Anthropology Journal 32, no. 1 (January 15, 2019): 8–15. http://dx.doi.org/10.26575/daj.v32i1.29.
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The present study assesses the global distribution of marginal accessory tubercles of the maxillary premolars. This trait, despite constituting one of the variables standardized by Turner and colleagues (1991), has received little attention in morphological studies. Frequencies were calculated from data sheets collected by Christy G. Turner II for mesial, distal, and mesial + distal grades. Different geographic patterns were identified for both types of expression on the upper premolars. The patterned geographic distribution of these traits indicates their utility in biodistance investigations. In addition, the distinction between mesial and distal accessory tubercles specified by Scott and Irish (2017) is recommended, as these two traits exhibit different geographic patterns.
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Ghosh, Dibyendu, Malavika M., and Supriya Chakraborty. "Impact of viral silencing suppressors on plant viral synergism: a global agro-economic concern." Applied Microbiology and Biotechnology 105, no. 16-17 (August 2021): 6301–13. http://dx.doi.org/10.1007/s00253-021-11483-9.
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Fane, B., R. Villafane, A. Mitraki, and J. King. "Identification of global suppressors for temperature-sensitive folding mutations of the P22 tailspike protein." Journal of Biological Chemistry 266, no. 18 (June 1991): 11640–48. http://dx.doi.org/10.1016/s0021-9258(18)99005-8.
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Lee, S. C., H. Koh, and M. H. Yu. "Molecular properties of global suppressors of temperature-sensitive folding mutations in P22 tailspike endorhamnosidase." Journal of Biological Chemistry 266, no. 34 (December 1991): 23191–96. http://dx.doi.org/10.1016/s0021-9258(18)54482-3.
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Whitham, Steven A., Chunling Yang, and Michael M. Goodin. "Global Impact: Elucidating Plant Responses to Viral Infection." Molecular Plant-Microbe Interactions® 19, no. 11 (November 2006): 1207–15. http://dx.doi.org/10.1094/mpmi-19-1207.
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Viruses induce a variety of responses in host cells that are mediated by perturbation of different signaling pathways. Advances in our understanding of the functions of viral proteins, plant biology in general, as well as technologies for profiling gene expression have converged in recent years to provide new insight into the events occurring inside susceptible and resistant host cells in response to virus infection. These effects range from nonspecific changes in gene expression due to the general accumulation of viral proteins to those responses that are initiated by the specific interactions between virus and host proteins. Here, we discuss a variety of expression profiling methods and approaches that have been used to study the effects of viruses on host transcriptomes. These studies have identified distinct sets of genes that have altered expression profiles in response to viruses, including stress- and defense-related genes. The activities of viral RNA silencing suppressors and interference with hormone signaling or biogenesis also influence plant gene expression and lead to developmental abnormalities.
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Pashkova, Natasha, Natalie L. Catlett, Jennifer L. Novak, and Lois S. Weisman. "A Point Mutation in the Cargo-Binding Domain of Myosin V Affects Its Interaction with Multiple Cargoes." Eukaryotic Cell 4, no. 4 (April 2005): 787–98. http://dx.doi.org/10.1128/ec.4.4.787-798.2005.
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ABSTRACT Class V myosins move diverse intracellular cargoes, which attach via interaction of cargo-specific proteins to the myosin V globular tail. The globular tail of the yeast myosin V, Myo2p, contains two structural and functional subdomains. Subdomain I binds to the vacuole-specific protein, Vac17p, while subdomain II likely binds to an as yet unidentified secretory vesicle-specific protein. All functions of Myo2p require the tight association of subdomains I and II, which suggests that binding of a cargo to one subdomain may inhibit cargo-binding to a second subdomain. Thus, two types of mutations are predicted to specifically affect a subset of Myo2p cargoes: first are mutations within a cargo-specific binding region; second are mutations that mimic the inhibited conformation of one of the subdomains. Here we analyze a point mutation in subdomain I, myo2-2(G1248D), which is likely to be this latter type of mutation. myo2-2 has no effect on secretory vesicle movement. The secretory vesicle binding site is in subdomain II. However, myo2-2 is impaired in several Myo2p-related functions. While subdomains I and II of myo2-2p tightly associate, there are measurable differences in the conformation of its globular tail. Based solely on the ability to restore vacuole inheritance, a set of intragenic suppressors of myo2-2 were identified. All suppressor mutations reside in subdomain I. Moreover, subdomain I and II interactions occurred in all suppressors, demonstrating the importance of subdomain I and II association for Myo2p function. Furthermore, 3 of the 10 suppressors globally restored all tested defects in myo2-2. This large proportion of global suppressors strongly suggests that myo2-2(G1248) causes a conformational change in subdomain I that simultaneously affects multiple cargoes.
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Pinchefsky, Elana, Laurence Laneuville, and Myriam Srour. "Distal 22q11.2 Microduplication." Child Neurology Open 4 (January 1, 2017): 2329048X1773765. http://dx.doi.org/10.1177/2329048x17737651.
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Distal chromosome 22q11.2 microduplications are associated with a wide range of phenotypes and unclear pathogenicity. The authors report on a 3-year-old girl with global developmental delay harboring a de novo 1.24 Mb distal chromosome 22q11.2 microduplication and a paternally inherited 0.25 Mb chromosome 4p14 microduplication. The authors review clinical features of 30 reported cases of distal 22q11.2 duplications. Common features include developmental delay (93%), neuropsychiatric features (26%), and nonspecific facial dysmorphisms (74%). In 70% of cases, the distal 22q11.2 duplications were inherited, and the majority of the carrier parents were phenotypically normal. Furthermore, 30% of probands carried an additional copy number variant. Review of the phenotype in individuals carrying microduplications involving similar low copy repeats (LCR) failed to establish any clear genotype–phenotype correlations. Distal 22q11.2 duplications represent a major challenge for genetic counseling and prediction of clinical consequences. Our report suggests a pathogenic role of distal 22q11.2 duplications and supports a “multiple hit” hypothesis underlying its variable expressivity and phenotypic severity.
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Agarwal, Anshu, Vikash Kansal, Humaira Farooqi, Ram Prasad, and Vijay Kumar Singh. "Epigallocatechin Gallate (EGCG), an Active Phenolic Compound of Green Tea, Inhibits Tumor Growth of Head and Neck Cancer Cells by Targeting DNA Hypermethylation." Biomedicines 11, no. 3 (March 5, 2023): 789. http://dx.doi.org/10.3390/biomedicines11030789.
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Head and neck cancers are among the deadliest cancers, ranked sixth globally in rates of high mortality and poor patient prognoses. The prevalence of head and neck squamous cell carcinoma (HNSCC) is associated with smoking and excessive alcohol consumption. Despite several advances in diagnostic and interventional methods, the morbidity of subjects with HNSCC has remained unchanged over the last 30 years. Epigenetic alterations, such as DNA hypermethylation, are commonly associated with several cancers, including HNSCC. Thus, epigenetic changes are considered promising therapeutic targets for chemoprevention. Here, we investigated the effect of EGCG on DNA hypermethylation and the growth of HNSCC. First, we assessed the expression levels of global DNA methylation in HNSCC cells (FaDu and SCC-1) and observed enhanced methylation levels compared with normal human bronchial epithelial cells (NHBE). Treatment of EGCG to HNSCC cells significantly inhibited global DNA hypermethylation by up to 70–80% after 6 days. Inhibition of DNA hypermethylation in HNSCC cells was confirmed by the conversion of 5-methylcytosine (5-mc) into 5-hydroxy methylcytosine (5hmC). DNA methyltransferases regulate DNA methylation. Next, we checked the effect of EGCG on the expression levels of DNA methyltransferases (DNMTs) and DNMT activity. Treatment of EGCG to HNSCC cells significantly reduced DNMT activity to 60% in SCC-1 and 80% in FaDu cells. The protein levels of DNMT3a and DNMT3b were downregulated in both cell lines after EGCG treatment. EGCG treatment to HNSCC cells reactivated tumor suppressors and caused decreased cell proliferation. Our in vivo study demonstrated that administration of EGCG (0.5%, w/w) as a supplement within an AIN76A diet resulted in inhibition of tumor growth in FaDu xenografts in nude mice (80%; p < 0.01) compared with non-EGCG-treated controls. The growth inhibitory effect of dietary EGCG on the HNSCC xenograft tumors was associated with the inhibition of DNMTs and reactivation of silenced tumor suppressors. Together, our study provides evidence that EGCG acts as a DNA demethylating agent and can reactivate epigenetically silenced tumor suppressors to inhibit the growth of HNSCC cells.
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Ott, Christopher J., Gang Lu, Jaime Reyes, Charles Y. Lin, William G. Kaelin, and James E. Bradner. "Disruption of the Ikaros-Mediated Gene Expression Program in Multiple Myeloma with Immunomodulatory Agents." Blood 124, no. 21 (December 6, 2014): 420. http://dx.doi.org/10.1182/blood.v124.21.420.420.
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Abstract The close chemical analogues lenalidomide and pomalidomide are immunomodulating drugs (IMiDs) that possess antineoplastic activity in multiple myeloma (MM) and other hematologic malignancies. IMiDs exert intrinsic antiproliferative effects on MM cells at least in part through direct interaction with intracellular cereblon. Cereblon (CRBN) is a component of the E3 ubiquitin ligase complex that also includes CUL4, RBX1, and DDB1 – together referred to as CRL4CRBN. Direct binding of IMiDs to a small hydrophobic pocket of the CRBN carboxy-terminal domain induces altered ubiquitinylation activity, including disrupted autoubiquitinylation of CRL4CRBN (Ito et al. Science, 2010; Fischer et al. Nature, 2014). Recently, we and others described the zinc finger transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) as endogenous targets of CRL4CRBN ubiquitinylation in MM cells (Lu et al. Science, 2014; Kronke et al. Science, 2014). We found that treatment of MM cells with lenalidomide (LEN) causes increased ubiquitinylation of IKZF1 and IKZF3 by CRL4CRBN, and targets them for degradation by the proteasome. This loss of IKZF1/3 was both necessary and sufficient to observe the cellular antiproliferative effects of LEN, suggesting that this a primary mechanism of IMiD activity in MM. However, it remains unclear how depletion of these transcription factors ultimately leads to reduced proliferation of myeloma cells. Several gene products are known to be perturbed in MM cells upon IMiD treatment, including transcriptional downregulation of the master regulator transcription factor IRF4 (Zhu et al. Blood, 2011; Lu et al. Science, 2014). Yet rescue experiments with exogenous expression of IRF4 cannot fully rescue effects of IMiD treatment in MM cells, suggesting that other IKZF1/3 target genes play a role in the antiproliferative effects of IMiDs. Here we use complementary gene expression and genomic approaches to discern the global effects of IMiD treatment on MM cells. Using chromatin-immunoprecipitation followed by high-throughput sequencing (ChIP-seq), we have determined the genome-wide binding profile of both IKZF1 and IKZF3 in MM cells. We find both IKZF1 and IKZF3 occupy genomic regions including promoters, gene bodies, and distal enhancer elements. In MM cells, IKZF1 and IKZF3 enrichment almost always co-occurs, corresponding to reports of IKZF1/3 heterodimers facilitating transcriptional programs in lymphoid cells (Morgan et al. EMBO, 1997). Treatment of MM cells with LEN results in a dramatic decrease of both IKZF1 and IKZF3 binding to the genome at promoters and enhancers. Additionally, we performed ChIP-seq on RNA polymerase II (RNAPII) after LEN treatment in order to determine how IMiD-mediated IKZF1/3 depletion affects cellular transcriptional activity. Loss of IKZF1/3 binding to target genes most often correlates with increased density of RNAPII in gene bodies, suggesting transcriptional derepression of IKZF1/3 target genes. This observation was confirmed with genome-wide expression analysis by microarray. Among the derepressed target genes were genes with known tumor suppressor activity including CDKN1A, KLF6, and TXNIP. The IRF4 locus was also found to be a direct target of IKZF1/3, including binding to a large distal enhancer region upstream of the IRF4 coding region. Yet unlike most other IKZF1/3 target genes, RNAPII density within the IRF4 gene body is significantly decreased upon LEN treatment, suggesting that unique transcriptional regulatory mechanisms function at this locus that are distinct from other IKZF1/3 targets. Knockdown of IKZF1 and IKZF3 expression by shRNAs results in increased TXNIP and decreased IRF4 mRNA and protein expression, further suggesting that IMiD-mediated degradation of IKZF1/3 leads to opposite effects on these genes. TXNIP encodes the thioredoxin binding protein, which increases cellular reactive oxygen species and promotes G0/G1 cell cycle arrest. Forced exogenous overexpression of TXNIP inhibits MM cell growth, indicating a potential additional mechanism of IMiD activity. These studies define the IKZF1/3-mediated transcription program in MM cells and detail its perturbation by IMiDs. Ultimately these data will be informative for understanding the downstream effectors of intrinsic IMiD activity in hematologic malignancies, and to further understand mechanisms for acquired or innate resistance to these therapies. Disclosures No relevant conflicts of interest to declare.
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Curtis, Daniel M., Cody S. Lee, Haroutioun H. Boyajian, Michael J. Lee, Megan Conti Mica, and Lewis L. Shi. "Effect of Global Fracture Care Billing on Distal Radius Fractures." Orthopedics 43, no. 5 (June 5, 2020): e471-e475. http://dx.doi.org/10.3928/01477447-20200521-10.
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Jayakumar, Prakash, Teun Teunis, Beatriz Giménez, Frederik Verstreken, Livio Di Mascio, and Jesse Jupiter. "AO Distal Radius Fracture Classification: Global Perspective on Observer Agreement." Journal of Wrist Surgery 06, no. 01 (August 8, 2016): 046–53. http://dx.doi.org/10.1055/s-0036-1587316.
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Guest, J. R., and I. T. Creaghan. "Further Studies with Lipoamide Dehydrogenase Mutants of Escherichia coli k12." Microbiology 81, no. 1 (January 1, 2000): 237–45. http://dx.doi.org/10.1099/00221287-81-1-237.
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The immunological properties of ten lipoamide dehydrogenase mutants of Escherichia coli were investigated with antiserum raised against purified lipoamide dehydrogenase. Seven mutants were CRM+ (cross-reacting material present) as they contained lipoamide dehydrogenase proteins exhibiting either complete or partial immunological identity with the wild-type protein. This indicates that at least seven of the mutations affect the lipoamide dehydrogenase structural gene (lpd). The remaining three mutants (CRM-) contained no detectable cross-reacting protein. None of the lpd mutations were sensitive to any of three different amber-suppressors. Genetic analysis by P1-transduction showed that all the lpd mutant sites were clustered very near the distal gene (aceF) of the ace region which specifies the dehydrogenase (aceE) and transacetylase (aceF) components of the pyruvate dehydrogenase multienzyme complex. Calculations based on the recombination frequency between an aceF mutant and the nearest lpd mutant site support the conclusion that apart from the possible presence of a regulatory element, the aceF and lpd genes are contiguous.
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Brown, Nicholas G., Jeanine M. Pennington, Wanzhi Huang, Tulin Ayvaz, and Timothy Palzkill. "Multiple Global Suppressors of Protein Stability Defects Facilitate the Evolution of Extended-Spectrum TEM β-Lactamases." Journal of Molecular Biology 404, no. 5 (December 2010): 832–46. http://dx.doi.org/10.1016/j.jmb.2010.10.008.
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Kyrychko, B. P., and V. V. Semirenko. "Efficiency of complex pig therapy with pathology of the distal department of the limbs." Scientific Messenger of LNU of Veterinary Medicine and Biotechnologies 22, no. 98 (August 22, 2020): 3–8. http://dx.doi.org/10.32718/nvlvet9801.
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Studies have been conducted to establish the dynamics of the course of treatment of purulent-inflammatory process of distal limb in pigs. The treatment algorithm was presented by two schemes: classic (I – experimental screw) and experimental (II – experimental group). Among the morphological parameters investigated: hemoglobin level, erythrocyte sedimentation rate (ESR), hematocrit, leukograms, total erythrocytes and leukocytes in the blood. To determine the immunobiological activity of the body of sick pigs, serum T: lymphocytes (CD2, CD3), T-helper cells (CD4), T-suppressors/killers (CD8), IRI (T-help/T-sup.), NK cells (CD16), B-lymphocytes (CD22), immunoglobulins A, M, G, CEC and phagocytic index. Research objectives – determining the effectiveness of treatment regimens algorithm for morphological and immunological composition of the blood in different forms of lymphoma disease distal extremities in pigs. Manifestation effector function was observed a decrease in lymphocytes, proliferation and differentiation of corresponding antibodies of the immune system of pigs. Inhibition of regulatory function in the inflammatory process reduces the mechanisms of formation of biologically active compounds “chemotaxis factor”, “transfer factor”, “phagocytosis factor”, migration of neutrophils and macrophages. The decrease in the concentration of NK cells in 2 times, with the pathology open wound, indicates a decrease in the process of opsonization (antibody-dependent cellular cytotoxicity) due to the lack of immune response to pathogens in the inflammatory cell. In abscesses, purulent pododermatitis and laminitis, NK cells decrease 1.5 times with the indirect manifestation of specific cytotoxic cells (B-lymphocytes, macrophages). It is determined that the drug “Trifuzol 1%” activates effector and reparative function of specific components of immune activity (T and B lymphocytes, population of T cells, NK cells). The results of these studies in the article thoroughly show the dynamics of changes in morphological and immunological status of pigs for diseases of the musculoskeletal system of the distal extremity. The results will facilitate the work of veterinary practitioners in the treatment of nosological forms of distal limb diseases in pigs.
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Asslaber, Daniela, Josefina Piñón Hofbauer, Richard Greil, and Alexander Egle. "MicroRNAs as biomarkers for the diagnosis and prognosis of human cancer." Journal of Nucleic Acids Investigation 1, no. 1 (December 13, 2010): 14. http://dx.doi.org/10.4081/jnai.2010.2130.
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miRNAs are small-noncoding RNA molecules that regulate gene expression on a posttranscriptional level. A number of oncogenes and tumor suppressors were found to be targets of miRNAs and global miRNA expression signatures were able to distinguish between cancerous and non-cancerous tissues. Therefore it was not surprising that some miRNAs could be linked to the pathogenesis of cancer. In this review we provide an overview of the use of microRNAs as diagnostic and prognostic tools in cancer and focus on the use of miRNA expression as biomarker for disease activity.
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Lycan, D., G. Mikesell, M. Bunger, and L. Breeden. "Differential effects of Cdc68 on cell cycle-regulated promoters in Saccharomyces cerevisiae." Molecular and Cellular Biology 14, no. 11 (November 1994): 7455–65. http://dx.doi.org/10.1128/mcb.14.11.7455-7465.1994.
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Swi4 and Swi6 form a complex which is required for Start-dependent activation of HO and for high-level expression of G1 cyclin genes CLN1 and CLN2. To identify other regulators of this pathway, we screened for dominant, recessive, conditional, and allele-specific suppressors of swi4 mutants. We isolated 16 recessive suppressors that define three genes, SSF1, SSF5, and SSF9 (suppressor of swi four). Mutations in all three genes bypass the requirement for both Swi4 and Swi6 for HO transcription and activate transcription from reporter genes lacking upstream activating sequences (UASs). SSF5 is allelic with SIN4 (TSF3), a gene implicated in global repression of transcription and chromatin structure, and SSF9 is likely to be a new global repressor of transcription. SSF1 is allelic with CDC68 (SPT16). cdc68 mutations have been shown to increase expression from defective promoters, while preventing transcription from other intact promoters, including CLN1 and CLN2. We find that CDC68 is a required activator of both SWI4 and SWI6, suggesting that CDC68's role at the CLN promoters may be indirect. The target of CDC68 within the SWI4 promoter is complex in that known activating elements (MluI cell cycle boxes) in the SWI4 promoter are required for CDC68 dependence but only within the context of the full-length promoter. This result suggests that there may be both a chromatin structure and a UAS-specific component to Cdc68 function at SWI4. We suggest that Cdc68 functions both in the assembly of repressive complexes that form on many intact promoters in vivo and in the relief of this repression during gene activation.
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Lycan, D., G. Mikesell, M. Bunger, and L. Breeden. "Differential effects of Cdc68 on cell cycle-regulated promoters in Saccharomyces cerevisiae." Molecular and Cellular Biology 14, no. 11 (November 1994): 7455–65. http://dx.doi.org/10.1128/mcb.14.11.7455.
Full textAbstract:
Swi4 and Swi6 form a complex which is required for Start-dependent activation of HO and for high-level expression of G1 cyclin genes CLN1 and CLN2. To identify other regulators of this pathway, we screened for dominant, recessive, conditional, and allele-specific suppressors of swi4 mutants. We isolated 16 recessive suppressors that define three genes, SSF1, SSF5, and SSF9 (suppressor of swi four). Mutations in all three genes bypass the requirement for both Swi4 and Swi6 for HO transcription and activate transcription from reporter genes lacking upstream activating sequences (UASs). SSF5 is allelic with SIN4 (TSF3), a gene implicated in global repression of transcription and chromatin structure, and SSF9 is likely to be a new global repressor of transcription. SSF1 is allelic with CDC68 (SPT16). cdc68 mutations have been shown to increase expression from defective promoters, while preventing transcription from other intact promoters, including CLN1 and CLN2. We find that CDC68 is a required activator of both SWI4 and SWI6, suggesting that CDC68's role at the CLN promoters may be indirect. The target of CDC68 within the SWI4 promoter is complex in that known activating elements (MluI cell cycle boxes) in the SWI4 promoter are required for CDC68 dependence but only within the context of the full-length promoter. This result suggests that there may be both a chromatin structure and a UAS-specific component to Cdc68 function at SWI4. We suggest that Cdc68 functions both in the assembly of repressive complexes that form on many intact promoters in vivo and in the relief of this repression during gene activation.
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Chen, Y., and B. K. Tye. "The yeast Mcm1 protein is regulated posttranscriptionally by the flux of glycolysis." Molecular and Cellular Biology 15, no. 8 (August 1995): 4631–39. http://dx.doi.org/10.1128/mcb.15.8.4631.
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Mcm1 is a multifunctional protein which plays a role both in the initiation of DNA replication and in the transcriptional regulation of diverse genes in Saccharomyces cerevisiae. The mcm1-1 mutation results in instability of minichromosomes and alpha-specific sterility. Second-site suppressors that restore minichromosome stability but not fertility to the mcm1-1 mutant were isolated. Two of the suppressors, pgm1-1 and pgm1-2, are mutant alleles of PGM1 which encodes a glycolytic enzyme, phosphoglycerate mutase. We show that the pgm1-1 mutation suppresses the minichromosome maintenance (Mcm) defect by increasing the protein activity or level of Mcm1-1 posttranscriptionally. This increase in the intracellular Mcm1-1 activity is sufficient to suppress the Mcm defect but only minimally suppresses the mating defect. Mutations in genes encoding other glycolytic enzymes, such as eno2::URA3, can also suppress the Mcm phenotype of mcm1-1. Suppression by these glycolytic enzyme mutations correlates with a reduced rate of glycolysis rather than a reduced rate of cell growth. This study suggests that in response to changes in their nutritional states yeast cells may attain homeostasis by modulating the activity of global regulators like Mcm1, which plays a central role in the regulation of energy-expensive anabolic processes.
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Xing, Huiqin, and Jianyu Yang. "WPL-Based Constraint for 3D Human Pose Estimation from a Single Depth Image." Sensors 22, no. 23 (November 22, 2022): 9040. http://dx.doi.org/10.3390/s22239040.
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Three-dimensional human pose estimation from depth maps is a fast-growing research area in computer vision. The distal joints of the human body are more flexible than the proximal joints, making it more difficult to estimate the distal joints. However, most existing methods ignore the difference between the distal joints and proximal joints. Moreover, the distal joint can be constrained by the proximal joint on the same kinematic chain. In our work, we model the human skeleton as the tree structure called the human-tree. Then, motivated by the WPL (weighted path length) in the data structure, we propose a WPL-based loss function to constrain the distal joints with the proximal joints in a global-to-local manner. Extensive experiments on benchmarks demonstrate that our method can effectively improve the performance of the distal joints.
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Gubb, David, John Roote, Jennifer Trenear, Darin Coulson, and Michael Ashburner. "Topological Constraints on Transvection Between white Genes Within the Transposing Element TE35B in Drosophila melanogaster." Genetics 146, no. 3 (July 1, 1997): 919–37. http://dx.doi.org/10.1093/genetics/146.3.919.
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The transposable element TE35B carries two copies of the white (w) gene at 35B1.2 on the second chromosome. These w genes are suppressed in a zeste-1 (z1) mutant background in a synapsis-dependent manner. Single-copy derivatives of the original TE35B stock give red eyes when heterozygous, but zeste eyes when homozygous. TE35B derivatives carrying single, double or triple copies of w were crossed to generate flies carrying from two to five ectopic w genes. Within this range, z1-mediated suppression is insensitive to copynumber and does not distinguish between w genes that are in cis or in trans. Suppression does not require the juxtaposition of even numbers of w genes, but is extremely sensitive to chromosomal topology. When arranged in a tight cluster, in triple-copy TE derivatives, w genes are non-suppressible. Breakpoints falling within TE35B and separating two functional w genes act as partial suppressors of z1. Similarly, breakpoints immediately proximal or distal to both w genes give partial suppression. This transvection-dependent downregulation of w genes may result from mis-activation of the X-chromosome dosage compensation mechanism.
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Ivanschitz, Lisa, Yuki Takahashi, Florence Jollivet, Olivier Ayrault, Morgane Le Bras, and Hugues de Thé. "PML IV/ARF interaction enhances p53 SUMO-1 conjugation, activation, and senescence." Proceedings of the National Academy of Sciences 112, no. 46 (November 2, 2015): 14278–83. http://dx.doi.org/10.1073/pnas.1507540112.
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Promyelocytic leukemia protein (PML) nuclear bodies (NBs) recruit multiple partners, including p53 and many of its regulators. NBs are believed to facilitate several posttranslational modifications and are key regulators of senescence. PML, the organizer of NBs, is expressed as a number of splice variants that all efficiently recruit p53 partners. However, overexpression of only one of them, PML IV, triggers p53-driven senescence. Here, we show that PML IV specifically binds ARF, a key p53 regulator. Similar to ARF, PML IV enhances global SUMO-1 conjugation, particularly that of p53, resulting in p53 stabilization and activation. ARF interacts with and stabilizes the NB-associated UBC9 SUMO-conjugating enzyme, possibly explaining PML IV-enhanced SUMOylation. These results unexpectedly link two key tumor suppressors, highlighting their convergence for global control of SUMO conjugation, p53 activation, and senescence induction.
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Casalino, Laura, and Pasquale Verde. "Multifaceted Roles of DNA Methylation in Neoplastic Transformation, from Tumor Suppressors to EMT and Metastasis." Genes 11, no. 8 (August 12, 2020): 922. http://dx.doi.org/10.3390/genes11080922.
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Among the major mechanisms involved in tumorigenesis, DNA methylation is an important epigenetic modification impacting both genomic stability and gene expression. Methylation of promoter-proximal CpG islands (CGIs) and transcriptional silencing of tumor suppressors represent the best characterized epigenetic changes in neoplastic cells. The global cancer-associated effects of DNA hypomethylation influence chromatin architecture and reactivation of repetitive elements. Moreover, recent analyses of cancer cell methylomes highlight the role of the DNA hypomethylation of super-enhancer regions critically controlling the expression of key oncogenic players. We will first summarize some basic aspects of DNA methylation in tumorigenesis, along with the role of dysregulated DNA methyltransferases and TET (Ten-Eleven Translocation)-family methylcytosine dioxygenases. We will then examine the potential contribution of epimutations to causality and heritability of cancer. By reviewing some representative genes subjected to hypermethylation-mediated silencing, we will survey their oncosuppressor functions and roles as biomarkers in various types of cancer. Epithelial-to-mesenchymal transition (EMT) and the gain of stem-like properties are critically involved in cancer cell dissemination, metastasis, and therapeutic resistance. However, the driver vs passenger roles of epigenetic changes, such as DNA methylation in EMT, are still poorly understood. Therefore, we will focus our attention on several aspects of DNA methylation in control of EMT and metastasis suppressors, including both protein-coding and noncoding genes.
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Gilroy, Kerry E., and John M. Pearce. "The role of local, distal, and global information in latent spatial learning." Journal of Experimental Psychology: Animal Learning and Cognition 40, no. 2 (April 2014): 212–24. http://dx.doi.org/10.1037/xan0000017.
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Maslowski, Merel, Antje S. Meyer, and Hans Rutger Bosker. "Eye-tracking the time course of distal and global speech rate effects." Journal of Experimental Psychology: Human Perception and Performance 46, no. 10 (October 2020): 1148–63. http://dx.doi.org/10.1037/xhp0000838.
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Skiba, Marcin W., Timothy S. George, Elizabeth M. Baggs, and Tim J. Daniell. "Plant influence on nitrification." Biochemical Society Transactions 39, no. 1 (January 19, 2011): 275–78. http://dx.doi.org/10.1042/bst0390275.
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Modern agriculture has promoted the development of high-nitrification systems that are susceptible to major losses of nitrogen through leaching of nitrate and gaseous emissions of nitrogen oxide (NO and N2O), contributing to global warming and depletion of the ozone layer. Leakage of nitrogen from agricultural systems forces increased use of nitrogen fertilizers and causes water pollution and elevated costs of food production. Possible strategies for prevention of these processes involve various agricultural management approaches and use of synthetic inhibitors. Growing plants capable of producing nitrification suppressors could become a potentially superior method of controlling nitrification in the soil. There is a need to investigate the phenomenon of biological nitrification inhibition in arable crop species.
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Neigeborn, L., J. L. Celenza, and M. Carlson. "SSN20 is an essential gene with mutant alleles that suppress defects in SUC2 transcription in Saccharomyces cerevisiae." Molecular and Cellular Biology 7, no. 2 (February 1987): 672–78. http://dx.doi.org/10.1128/mcb.7.2.672-678.1987.
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Dominant and recessive mutations at the SSN20 locus were previously isolated as extragenic suppressors of mutations in three genes (SNF2, SNF5, and SNF6) that are required in trans to derepress invertase expression. All ssn20 alleles cause recessive, temperature-sensitive lethality. In this study we cloned the SSN20 gene, identified a 4.6-kilobase poly(A)-containing RNA, and showed that disruption of the gene is lethal in a haploid cell. Genetic mapping of SSN20 to a locus on chromosome VII 10 centimorgans distal to cly8 led to the finding that SSN20 is the same gene as SPT6, which affects expression of delta insertions in the 5' noncoding region of HIS4 (F. Winston, D. T. Chaleff, B. Valent, and G. R. Fink, Genetics 107:179-197, 1984). We also showed that an ssn20 mutation restored expression of secreted invertase from deletions of the SUC2 upstream regulatory region; ssn20 restored derepression of SUC2 mRNA in strains with a SUC2 upstream region deletion or a snf2 mutation. Increased or decreased gene dosage of SSN20 also suppressed defects that are suppressed by ssn20 missense mutations. These findings suggest that SSN20 plays a role in general transcriptional processes.