4,721 results match your criteria genetic suppressors

Sulfopin is a covalent inhibitor of Pin1 that blocks Myc-driven tumors in vivo.

Nat Chem Biol 2021 May 10. Epub 2021 May 10.

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.

The peptidyl-prolyl isomerase, Pin1, is exploited in cancer to activate oncogenes and inactivate tumor suppressors. However, despite considerable efforts, Pin1 has remained an elusive drug target. Here, we screened an electrophilic fragment library to identify covalent inhibitors targeting Pin1's active site Cys113, leading to the development of Sulfopin, a nanomolar Pin1 inhibitor. Read More

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CBFB cooperates with p53 to maintain TAp73 expression and suppress breast cancer.

PLoS Genet 2021 May 4;17(5):e1009553. Epub 2021 May 4.

Cancer and Stem Cell Epigenetics Section, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America.

The CBFB gene is frequently mutated in several types of solid tumors. Emerging evidence suggests that CBFB is a tumor suppressor in breast cancer. However, our understanding of the tumor suppressive function of CBFB remains incomplete. Read More

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Germline Structural Variations in Cancer Predisposition Genes.

Front Genet 2021 14;12:634217. Epub 2021 Apr 14.

Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.

In addition to single nucleotide variations and small-scale indels, structural variations (SVs) also contribute to the genetic diversity of the genome. SVs, such as deletions, duplications, amplifications, or inversions may also affect coding regions of cancer-predisposing genes. These rearrangements may abrogate the open reading frame of these genes or adversely affect their expression and may thus act as germline mutations in hereditary cancer syndromes. Read More

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mRNA Surveillance Complex PELOTA-HBS1 Regulates Phosphoinositide-Dependent Protein Kinase1 and Plant Growth.

Plant Physiol 2021 Apr 30. Epub 2021 Apr 30.

Joint Centre for Single Cell Biology, School of Agriculture and Biology, Shanghai Jiao Tong University, 200240 Shanghai, China.

The quality control system for messenger RNA (mRNA) is fundamental for cellular activities in eukaryotes. To elucidate the molecular mechanism of 3'-Phosphoinositide-Dependent Protein Kinase1 (PDK1), a master regulator that is essential throughout eukaryotic growth and development, we employed a forward genetic approach to screen for suppressors of the loss-of-function T-DNA insertion double mutant pdk1.1 pdk1. Read More

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Atypical E2Fs either Counteract or Cooperate with RB during Tumorigenesis Depending on Tissue Context.

Cancers (Basel) 2021 Apr 23;13(9). Epub 2021 Apr 23.

Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CT Utrecht, The Netherlands.

E2F-transcription factors activate many genes involved in cell cycle progression, DNA repair, and apoptosis. Hence, E2F-dependent transcription must be tightly regulated to prevent tumorigenesis, and therefore metazoan cells possess multiple E2F regulation mechanisms. The best-known is the Retinoblastoma protein (RB), which is mutated in many cancers. Read More

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Interpretative differences of combined cytogenetic and molecular profiling highlights differences between MRC and ELN classifications of AML.

Cancer Genet 2021 Apr 16;256-257:68-76. Epub 2021 Apr 16.

Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, United States.

Acute myeloid leukemia (AML) is typically characterized clinically for prognostic purposes using both cytogenetic and molecular characteristics. However, both cytogenetic and molecular risk stratification schemas are varied and few reports have studied correlations between these schemas. We have performed a single institution retrospective review of cytogenetic and molecular classifications of AMLs seen at Penn Medicine between 2013 and 2018. Read More

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Allele-specific suppression in C. elegans reveals details of EMS mutagenesis and a possible moonlighting interaction between the vesicular acetylcholine transporter and ERD2 receptors.

Genetics 2021 Apr 29. Epub 2021 Apr 29.

Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.

A missense mutant, unc-17(e245), which affects the Caenorhabditis elegans vesicular acetylcholine transporter UNC-17, has a severe uncoordinated phenotype, allowing efficient selection of dominant suppressors that revert this phenotype to wild-type. Such selections permitted isolation of numerous suppressors after EMS (ethyl methanesulfonate) mutagenesis, leading to demonstration of delays in mutation fixation after initial EMS treatment, as has been shown in T4 bacteriophage but not previously in eukaryotes. Three strong dominant extragenic suppressor loci have been defined, all of which act specifically on allele e245, which causes a G347R mutation in UNC-17. Read More

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Beyond direct Nrf2 activation; reinvestigating 1,2,4-oxadiazole scaffold as a master key unlocking the antioxidant cellular machinery for cancer therapy.

Eur J Med Chem 2021 Apr 16;220:113475. Epub 2021 Apr 16.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt. Electronic address:

Harnessing the antioxidant cellular machinery has sparked considerable interest as an efficient anticancer strategy. Activating Nrf2, the master switch of the cellular redox system, suppresses ROS, alleviates oxidative stress, and halts cancer progression. 1,2,4-oxadiazoles are iconic direct Nrf2 activators that disrupt Nrf2 interaction with its endogenous repressor Keap1. Read More

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MAPS: machine-assisted phenotype scoring enables rapid functional assessment of genetic variants by high-content microscopy.

BMC Bioinformatics 2021 Apr 20;22(1):202. Epub 2021 Apr 20.

Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, V6T1Z3, Canada.

Background: Genetic testing is widely used in evaluating a patient's predisposition to hereditary diseases. In the case of cancer, when a functionally impactful mutation (i.e. Read More

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Integrated mutational landscape analysis of uterine leiomyosarcomas.

Proc Natl Acad Sci U S A 2021 Apr;118(15)

Department of Pathology, University of Brescia, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia, 25100 Brescia, Italy.

Uterine leiomyosarcomas (uLMS) are aggressive tumors arising from the smooth muscle layer of the uterus. We analyzed 83 uLMS sample genetics, including 56 from Yale and 27 from The Cancer Genome Atlas (TCGA). Among them, a total of 55 Yale samples including two patient-derived xenografts (PDXs) and 27 TCGA samples have whole-exome sequencing (WES) data; 10 Yale and 27 TCGA samples have RNA-sequencing (RNA-Seq) data; and 11 Yale and 10 TCGA samples have whole-genome sequencing (WGS) data. Read More

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Epigenetic modulation and understanding of HDAC inhibitors in cancer therapy.

Life Sci 2021 Apr 16;277:119504. Epub 2021 Apr 16.

Department of Computer Science and Engineering, Koneru Lakshmaiah Education Foundation, Vaddeswaram, Andhra Pradesh, India.

The role of genetic and epigenetic factors in tumor initiation and progression is well documented. Histone deacetylases (HDACs), histone methyl transferases (HMTs), and DNA methyl transferases. (DNMTs) are the main proteins that are involved in regulating the chromatin conformation. Read More

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Genetic analysis of the septal peptidoglycan synthase FtsWI complex supports a conserved activation mechanism for SEDS-bPBP complexes.

PLoS Genet 2021 Apr 15;17(4):e1009366. Epub 2021 Apr 15.

Department of Microbiology, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, HB, China.

SEDS family peptidoglycan (PG) glycosyltransferases, RodA and FtsW, require their cognate transpeptidases PBP2 and FtsI (class B penicillin binding proteins) to synthesize PG along the cell cylinder and at the septum, respectively. The activities of these SEDS-bPBPs complexes are tightly regulated to ensure proper cell elongation and division. In Escherichia coli FtsN switches FtsA and FtsQLB to the active forms that synergize to stimulate FtsWI, but the exact mechanism is not well understood. Read More

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Genetics animates structure: leveraging genetic interactions to study the dynamics of ribosome biogenesis.

Curr Genet 2021 Apr 12. Epub 2021 Apr 12.

Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA.

The assembly of eukaryotic ribosomes follows an assembly line-like pathway in which numerous trans-acting biogenesis factors act on discrete pre-ribosomal intermediates to progressively shape the nascent subunits into their final functional architecture. Recent advances in cryo-electron microscopy have led to high-resolution structures of many pre-ribosomal intermediates; however, these static snapshots do not capture the dynamic transitions between these intermediates. To this end, molecular genetics can be leveraged to reveal how the biogenesis factors drive these dynamic transitions. Read More

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Genetic manipulation and immortalized culture of ex vivo primary human germinal center B cells.

Nat Protoc 2021 May 9;16(5):2499-2519. Epub 2021 Apr 9.

Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.

Next-generation sequencing has transformed our knowledge of the genetics of lymphoid malignancies. However, limited experimental systems are available to model the functional effects of these genetic changes and their implications for therapy. The majority of mature B-cell malignancies arise from the germinal center (GC) stage of B-cell differentiation. Read More

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Cyclic di-AMP Oversight of Counter-Ion Osmolyte Pools Impacts Intrinsic Cefuroxime Resistance in Lactococcus lactis.

mBio 2021 04 8;12(2). Epub 2021 Apr 8.

School of Agriculture and Food Sciences, University of Queensland, Brisbane, Queensland, Australia

The broadly conserved cyclic di-AMP (c-di-AMP) is a conditionally essential bacterial second messenger. The pool of c-di-AMP is fine-tuned through diadenylate cyclase and phosphodiesterase activities, and direct binding of c-di-AMP to proteins and riboswitches allows the regulation of a broad spectrum of cellular processes. c-di-AMP has a significant impact on intrinsic β-lactam antibiotic resistance in Gram-positive bacteria; however, the reason for this is currently unclear. Read More

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Genomic characterization of small cell carcinomas of the uterine cervix.

Mol Oncol 2021 Apr 8. Epub 2021 Apr 8.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Small cell carcinoma (SCC) of the uterine cervix is a rare and aggressive form of neuroendocrine carcinoma, which resembles small cell lung cancer (SCLC) in its histology and poor survival rate. Here we sought to define the genetic underpinning of SCCs of the uterine cervix and compare their mutational profiles with those of human papillomavirus (HPV)-positive head and neck squamous cell carcinomas, HPV-positive cervical carcinomas and SCLCs using publicly available data. Using a combination of whole-exome and targeted massively parallel sequencing, we found that the nine uterine cervix SCCs, which were HPV18-positive (n=8) or HPV16-positive (n=1), harbored a low mutation burden, few copy number alterations and other than TP53 in two cases no recurrently mutated genes. Read More

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Prognostic Value of microRNA-221/2 and 17-92 Families in Primary Glioblastoma Patients Treated with Postoperative Radiotherapy.

Int J Mol Sci 2021 Mar 15;22(6). Epub 2021 Mar 15.

German Cancer Consortium (DKTK) Core-Center, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.

MicroRNAs (miRs) are non-coding master regulators of transcriptome that could act as tumor suppressors (TSs) or oncogenes (oncomiRs). We aimed to systematically investigate the relevance of miRs as prognostic biomarkers in primary glioblastoma multiforme (GBM) treated with postoperative radio(chemo)therapy (PORT). For hypothesis generation, tumor miR expression by Agilent 8x15K human microRNA microarrays and survival data from 482 GBM patients of The Cancer Genome Atlas (TCGA cohort) were analyzed using Cox-PH models. Read More

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Epigenetic Control of Infant B Cell Precursor Acute Lymphoblastic Leukemia.

Int J Mol Sci 2021 Mar 18;22(6). Epub 2021 Mar 18.

Lymphocyte Development and Disease Group, Josep Carreras Leukaemia Research Institute (IJC), Ctra. de Can Ruti, Camí de les Escoles s/n, 08916 Barcelona, Spain.

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a highly aggressive malignancy, with poorer prognosis in infants than in adults. A genetic signature has been associated with this outcome but, remarkably, leukemogenesis is commonly triggered by genetic alterations of embryonic origin that involve the deregulation of chromatin remodelers. This review considers in depth how the alteration of epigenetic profiles (at DNA and histone levels) induces an aberrant phenotype in B lymphocyte progenitors by modulating the oncogenic drivers and tumor suppressors involved in key cancer hallmarks. Read More

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Upregulation of the pathogenic transcription factor SPI1/PU.1 in tuberous sclerosis complex and focal cortical dysplasia by oxidative stress.

Brain Pathol 2021 Mar 30:e12949. Epub 2021 Mar 30.

Department of (Neuro)Pathology, Amsterdam Neuroscience, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

Tuberous sclerosis complex (TSC) is a congenital disorder characterized by cortical malformations and concomitant epilepsy caused by loss-of-function mutations in the mTOR suppressors TSC1 or TSC2. While the underlying molecular changes caused by mTOR activation in TSC have previously been investigated, the drivers of these transcriptional change have not been fully elucidated. A better understanding of the perturbed transcriptional regulation could lead to the identification of novel pathways for therapeutic intervention not only in TSC, but other genetic epilepsies in which mTOR activation plays a key role, such as focal cortical dysplasia 2b (FCD). Read More

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A tobacco ringspot virus-based vector system for gene and microRNA function studies in cucurbits.

Plant Physiol 2021 Mar 25. Epub 2021 Mar 25.

Shandong Provincial Key Laboratory of Agricultural Microbiology, Department of Plant Pathology, College of Plant Protection, Shandong Agricultural University, Tai'an, Shandong 271018, China.

Cucurbits are economically important crops worldwide. The genomic data of many cucurbits are now available. However, functional analyses of cucurbit genes and non-coding RNAs have been impeded because genetic transformation is difficult for many cucurbitaceous plants. Read More

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STK3/STK4 signalling in adipocytes regulates mitophagy and energy expenditure.

Nat Metab 2021 03 23;3(3):428-441. Epub 2021 Mar 23.

College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.

Obesity reduces adipocyte mitochondrial function, and expanding adipocyte oxidative capacity is an emerging strategy to improve systemic metabolism. Here, we report that serine/threonine-protein kinase 3 (STK3) and STK4 are key physiological suppressors of mitochondrial capacity in brown, beige and white adipose tissues. Levels of STK3 and STK4, kinases in the Hippo signalling pathway, are greater in white than brown adipose tissues, and levels in brown adipose tissue are suppressed by cold exposure and greatly elevated by surgical denervation. Read More

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Mucin O-glycans suppress quorum-sensing pathways and genetic transformation in Streptococcus mutans.

Nat Microbiol 2021 May 18;6(5):574-583. Epub 2021 Mar 18.

Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.

Mucus barriers accommodate trillions of microorganisms throughout the human body while preventing pathogenic colonization. In the oral cavity, saliva containing the mucins MUC5B and MUC7 forms a pellicle that coats the soft tissue and teeth to prevent infection by oral pathogens, such as Streptococcus mutans. Salivary mucin can interact directly with microorganisms through selective agglutinin activity and bacterial binding, but the extent and basis of the protective functions of saliva are not well understood. Read More

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The landscape of the heritable cancer genome.

Cancer Res 2021 Mar 17. Epub 2021 Mar 17.

School of Biological Sciences, University of Edinburgh

Genome-wide association studies (GWAS) have found hundreds of single nucleotide polymorphisms (SNPs) associated with increased risk of cancer. However, the amount of heritable risk explained by SNPs is limited, leaving most of cancer heritability unexplained. Tumor sequencing projects have shown that causal mutations are enriched in genic regions. Read More

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VAP-RELATED SUPPRESSORS OF TOO MANY MOUTHS (VST) family proteins are regulators of root system architecture.

Plant Physiol 2021 Mar;185(2):457-468

Department of Biology, Duke University, Durham, NC 27708, USA.

Root system architecture (RSA) is a key factor in the efficiency of nutrient capture and water uptake in plants. Understanding the genetic control of RSA will be useful in minimizing fertilizer and water usage in agricultural cropping systems. Using a hydroponic screen and a gel-based imaging system, we identified a rice (Oryza sativa) gene, VAP-RELATED SUPPRESSOR OF TOO MANY MOUTHS1 (OsVST1), which plays a key role in controlling RSA. Read More

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Long non-coding RNA signatures as predictors of prognosis in thyroid cancer: a narrative review.

Ann Transl Med 2021 Feb;9(4):359

Department of Thyroid and Parathyroid Surgery, West China Hospital, Sichuan University, Chengdu, China.

Thyroid cancer (TC) is the most common endocrine malignancy, with high incidence rates in recent decades. Most TC cases have good prognoses, but a high risk of recurrence and metastases poses challenges, especially for patients with high-risk factors. Currently used prognostic markers for TC involve a combination of genetic factors and overexpressed proteins. Read More

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February 2021

The Role of Replication Clamp-Loader Protein HolC of Escherichia coli in Overcoming Replication/Transcription Conflicts.

mBio 2021 03 9;12(2). Epub 2021 Mar 9.

Department of Biology, Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, Massachusetts, USA

In , DNA replication is catalyzed by an assembly of proteins, the DNA polymerase III holoenzyme. This complex includes the polymerase and proofreading subunits, the processivity clamp, and clamp loader complex. The gene encodes an accessory protein (known as χ) to the core clamp loader complex and is the only protein of the holoenzyme that binds to single-strand DNA binding protein, SSB. Read More

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Identification of PI3K-AKT signaling as the dominant altered pathway in intestinal type ampullary cancers through whole-exome sequencing.

J Pathol Transl Med 2021 Mar 9. Epub 2021 Mar 9.

Departments of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.

Background: The genetic landscape of intestinal (INT) and pancreatobiliary (PB) type ampullary cancer (AC) has been evolving with distinct as well as overlapping molecular profiles.

Materials And Methods: We performed whole-exome sequencing in 37 cases of AC to identify the targetable molecular profiles of INT and PB tumors. Paired tumor-normal sequencing was performed on the HiSeq 2500 Illumina platform. Read More

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Descriptive and Functional Genomics in Acute Myeloid Leukemia (AML): Paving the Road for a Cure.

Cancers (Basel) 2021 Feb 11;13(4). Epub 2021 Feb 11.

Université de Paris, APHP, Hôpital Saint-Louis, 75010 Paris, France.

Over the past decades, genetic advances have allowed a more precise molecular characterization of AML with the identification of novel oncogenes and tumor suppressors as part of a comprehensive AML molecular landscape. Recent advances in genetic sequencing tools also enabled a better understanding of AML leukemogenesis from the preleukemic state to posttherapy relapse. These advances resulted in direct clinical implications with the definition of molecular prognosis classifications, the development of treatment recommendations based on minimal residual disease (MRD) measurement and the discovery of novel targeted therapies, ultimately improving AML patients' overall survival. Read More

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February 2021

Current Knowledge on Genomic Profiling of Upper Tract Urothelial Carcinoma.

Genes (Basel) 2021 Feb 25;12(3). Epub 2021 Feb 25.

Urology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.

Recent research in next-generation sequencing characterized the genomic landscape of urothelial cancer. However, the majority of the studies focused on bladder cancer (BC). Upper urinary tract urothelial carcinomas (UTUC) and BC share some histological characteristics, but, considering the differences in terms of embryologic precursors, epidemiology, genetics, medical and surgical management and response to therapy, UTUC and BC should be considered as two distinct diseases. Read More

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February 2021

Integrative pan cancer analysis reveals epigenomic variation in cancer type and cell specific chromatin domains.

Nat Commun 2021 03 3;12(1):1419. Epub 2021 Mar 3.

Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA.

Epigenetic mechanisms contribute to the initiation and development of cancer, and epigenetic variation promotes dynamic gene expression patterns that facilitate tumor evolution and adaptation. While the NCI-60 panel represents a diverse set of human cancer cell lines that has been used to screen chemical compounds, a comprehensive epigenomic atlas of these cells has been lacking. Here, we report an integrative analysis of 60 human cancer epigenomes, representing a catalog of activating and repressive histone modifications. Read More

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