USP9X Regulates Centrosome Duplication and Promotes Breast Carcinogenesis
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University of Leicester, Msc Medical Statistics, Thesis, Wilmar
Thesis MSc in Medical Statistics Department of Health Sciences University of Leicester, United Kingdom Application of Bayesian hierarchical generalized linear models using weakly informative prior distributions to identify rare genetic variant effects on blood pressure Wilmar Igl March 2015 Summary Background Currently rare genetic variants are discussed as a source of \missing heritability" of complex traits. Bayesian hierarchical models were proposed as an efficient method for the estimation and aggregation of conditional effects of rare variants. Here, such models are applied to identify rare variant effects on blood pressure. Methods Empirical data provided by the Genetic Analysis Workshop 19 (2014) included 1,851 Mexican-American individuals with diastolic blood pressure (DBP), systolic blood pressure (SBP), hypertension (HTN) and 461,868 variants from whole- exome sequencing of odd-numbered chromosomes. Bayesian hierarchical generalized linear models using weakly informative prior distributions were applied. Results Associations of rare variants chr1:204214013 (estimate = 39.6, Credible In- terval (CrI) 95% = [25.3, 53.9], Bayesian p = 6:8 × 10−8) in the PLEKHA6 gene and chr11:118518698 (estimate = 32.2, CrI95% = [20.6, 43.9], Bayesian p = 7:0 × 10−8) in the PHLEDB1 gene were identified. Joint effects of grouped rare variants on DBP in 23 genes (Bayesian p = [8:8 × 10−14, 9:3 × 10−8]) and on SBP in 21 genes (Bayesian p = [8:6 × 10−12, 7:8 × 10−8]) in pathways related to hemostasis, sodi- um/calcium transport, ciliary activity, and others were found. No association with hypertension was detected. Conclusions Bayesian hierarchical generalized linear models with weakly informa- tive priors can successfully be applied in exome-wide genetic association analyses of rare variants. -
Ubiquitin-Mediated Control of ETS Transcription Factors: Roles in Cancer and Development
International Journal of Molecular Sciences Review Ubiquitin-Mediated Control of ETS Transcription Factors: Roles in Cancer and Development Charles Ducker * and Peter E. Shaw * Queen’s Medical Centre, School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, UK * Correspondence: [email protected] (C.D.); [email protected] (P.E.S.) Abstract: Genome expansion, whole genome and gene duplication events during metazoan evolution produced an extensive family of ETS genes whose members express transcription factors with a conserved winged helix-turn-helix DNA-binding domain. Unravelling their biological roles has proved challenging with functional redundancy manifest in overlapping expression patterns, a common consensus DNA-binding motif and responsiveness to mitogen-activated protein kinase signalling. Key determinants of the cellular repertoire of ETS proteins are their stability and turnover, controlled largely by the actions of selective E3 ubiquitin ligases and deubiquitinases. Here we discuss the known relationships between ETS proteins and enzymes that determine their ubiquitin status, their integration with other developmental signal transduction pathways and how suppression of ETS protein ubiquitination contributes to the malignant cell phenotype in multiple cancers. Keywords: E3 ligase complex; deubiquitinase; gene fusions; mitogens; phosphorylation; DNA damage 1. Introduction Citation: Ducker, C.; Shaw, P.E. Cell growth, proliferation and differentiation are complex, concerted processes that Ubiquitin-Mediated Control of ETS Transcription Factors: Roles in Cancer rely on careful regulation of gene expression. Control over gene expression is maintained and Development. Int. J. Mol. Sci. through signalling pathways that respond to external cellular stimuli, such as growth 2021, 22, 5119. https://doi.org/ factors, cytokines and chemokines, that invoke expression profiles commensurate with 10.3390/ijms22105119 diverse cellular outcomes. -
SNX17 Recruits USP9X to Antagonize MIB1-Mediated Ubiquitination and Degradation of PCM1 During Serum-Starvation-Induced Ciliogenesis
cells Article SNX17 Recruits USP9X to Antagonize MIB1-Mediated Ubiquitination and Degradation of PCM1 during Serum-Starvation-Induced Ciliogenesis Pengtao Wang 1,2,3,4, Jianhong Xia 2,3, Leilei Zhang 2,3, Shaoyang Zhao 2,3, Shengbiao Li 2,3, Haiyun Wang 2,3, Shan Cheng 4, Heying Li 2,3, Wenguang Yin 2,3, Duanqing Pei 2,3,5,* and Xiaodong Shu 2,3,4,5,6,* 1 School of Life Sciences, University of Science and Technology of China, Hefei 230027, China; [email protected] 2 CAS Key Laboratory of Regenerative Biology, South China Institutes for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; [email protected] (J.X.); [email protected] (L.Z.); [email protected] (S.Z.); [email protected] (S.L.); [email protected] (H.W.); [email protected] (H.L.); [email protected] (W.Y.) 3 Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou 510530, China 4 Hefei Institute of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; [email protected] 5 Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GRMH-GDL), Guangzhou 510005, China 6 Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou 511436, China * Correspondence: [email protected] (D.P.); [email protected] (X.S.); Tel.: +86-20-3201-5310 (X.S.) Academic Editor: Tomer Avidor-Reiss Received: 13 September 2019; Accepted: 27 October 2019; Published: 29 October 2019 Abstract: Centriolar satellites are non-membrane cytoplasmic granules that deliver proteins to centrosome during centrosome biogenesis and ciliogenesis. -
Inhibition of Mitochondrial Complex II in Neuronal Cells Triggers Unique
www.nature.com/scientificreports OPEN Inhibition of mitochondrial complex II in neuronal cells triggers unique pathways culminating in autophagy with implications for neurodegeneration Sathyanarayanan Ranganayaki1, Neema Jamshidi2, Mohamad Aiyaz3, Santhosh‑Kumar Rashmi4, Narayanappa Gayathri4, Pulleri Kandi Harsha5, Balasundaram Padmanabhan6 & Muchukunte Mukunda Srinivas Bharath7* Mitochondrial dysfunction and neurodegeneration underlie movement disorders such as Parkinson’s disease, Huntington’s disease and Manganism among others. As a corollary, inhibition of mitochondrial complex I (CI) and complex II (CII) by toxins 1‑methyl‑4‑phenylpyridinium (MPP+) and 3‑nitropropionic acid (3‑NPA) respectively, induced degenerative changes noted in such neurodegenerative diseases. We aimed to unravel the down‑stream pathways associated with CII inhibition and compared with CI inhibition and the Manganese (Mn) neurotoxicity. Genome‑wide transcriptomics of N27 neuronal cells exposed to 3‑NPA, compared with MPP+ and Mn revealed varied transcriptomic profle. Along with mitochondrial and synaptic pathways, Autophagy was the predominant pathway diferentially regulated in the 3‑NPA model with implications for neuronal survival. This pathway was unique to 3‑NPA, as substantiated by in silico modelling of the three toxins. Morphological and biochemical validation of autophagy markers in the cell model of 3‑NPA revealed incomplete autophagy mediated by mechanistic Target of Rapamycin Complex 2 (mTORC2) pathway. Interestingly, Brain Derived Neurotrophic Factor -
X-Linked Diseases: Susceptible Females
REVIEW ARTICLE X-linked diseases: susceptible females Barbara R. Migeon, MD 1 The role of X-inactivation is often ignored as a prime cause of sex data include reasons why women are often protected from the differences in disease. Yet, the way males and females express their deleterious variants carried on their X chromosome, and the factors X-linked genes has a major role in the dissimilar phenotypes that that render women susceptible in some instances. underlie many rare and common disorders, such as intellectual deficiency, epilepsy, congenital abnormalities, and diseases of the Genetics in Medicine (2020) 22:1156–1174; https://doi.org/10.1038/s41436- heart, blood, skin, muscle, and bones. Summarized here are many 020-0779-4 examples of the different presentations in males and females. Other INTRODUCTION SEX DIFFERENCES ARE DUE TO X-INACTIVATION Sex differences in human disease are usually attributed to The sex differences in the effect of X-linked pathologic variants sex specific life experiences, and sex hormones that is due to our method of X chromosome dosage compensation, influence the function of susceptible genes throughout the called X-inactivation;9 humans and most placental mammals – genome.1 5 Such factors do account for some dissimilarities. compensate for the sex difference in number of X chromosomes However, a major cause of sex-determined expression of (that is, XX females versus XY males) by transcribing only one disease has to do with differences in how males and females of the two female X chromosomes. X-inactivation silences all X transcribe their gene-rich human X chromosomes, which is chromosomes but one; therefore, both males and females have a often underappreciated as a cause of sex differences in single active X.10,11 disease.6 Males are the usual ones affected by X-linked For 46 XY males, that X is the only one they have; it always pathogenic variants.6 Females are biologically superior; a comes from their mother, as fathers contribute their Y female usually has no disease, or much less severe disease chromosome. -
Caracterización De Complejos CDK-Ciclina Atípicos Humanos Eva Quandt Herrera
Caracterización de complejos CDK-Ciclina atípicos humanos Eva Quandt Herrera ADVERTIMENT. La consulta d’aquesta tesi queda condicionada a l’acceptació de les següents condicions d'ús: La difusió d’aquesta tesi per mitjà del servei TDX (www.tesisenxarxa.net) ha estat autoritzada pels titulars dels drets de propietat intel·lectual únicament per a usos privats emmarcats en activitats d’investigació i docència. No s’autoritza la seva reproducció amb finalitats de lucre ni la seva difusió i posada a disposició des d’un lloc aliè al servei TDX. No s’autoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant al resum de presentació de la tesi com als seus continguts. En la utilització o cita de parts de la tesi és obligat indicar el nom de la persona autora. ADVERTENCIA. La consulta de esta tesis queda condicionada a la aceptación de las siguientes condiciones de uso: La difusión de esta tesis por medio del servicio TDR (www.tesisenred.net) ha sido autorizada por los titulares de los derechos de propiedad intelectual únicamente para usos privados enmarcados en actividades de investigación y docencia. No se autoriza su reproducción con finalidades de lucro ni su difusión y puesta a disposición desde un sitio ajeno al servicio TDR. No se autoriza la presentación de su contenido en una ventana o marco ajeno a TDR (framing). Esta reserva de derechos afecta tanto al resumen de presentación de la tesis como a sus contenidos. En la utilización o cita de partes de la tesis es obligado indicar el nombre de la persona autora. -
USP9X Monoclonal Antibody (M05A), Clone 5D7
USP9X monoclonal antibody (M05A), clone 5D7 Catalog # : H00008239-M05A 規格 : [ 200 uL ] List All Specification Application Image Product Mouse monoclonal antibody raised against a partial recombinant Western Blot (Tissue lysate) Description: USP9X. Immunogen: USP9X (NP_068706, 1 a.a. ~ 90 a.a) partial recombinant protein with GST tag. MW of the GST tag alone is 26 KDa. Sequence: MTATTRGSPVGGNDNQGQAPDGQSQPPLQQNQTSSPDSSNENSPATP PDEQGQGDAPPQLEDEEPAFPHTDLAKLDDMINRPRWVVPVLP enlarge Western Blot (Cell lysate) Host: Mouse Reactivity: Human Isotype: IgG1 Kappa Quality Control Antibody Reactive Against Recombinant Protein. enlarge Testing: Western Blot (Recombinant protein) ELISA Western Blot detection against Immunogen (35.64 KDa) . Storage Buffer: In ascites fluid Storage Store at -20°C or lower. Aliquot to avoid repeated freezing and thawing. Instruction: MSDS: Download Datasheet: Download Applications Western Blot (Tissue lysate) Page 1 of 3 2020/6/25 USP9X monoclonal antibody (M05A), clone 5D7. Western Blot analysis of USP9X expression in human placenta. Protocol Download Western Blot (Cell lysate) USP9X monoclonal antibody (M05A), clone 5D7. Western Blot analysis of USP9X expression in Jurkat(Cat # L017V1 ). Protocol Download Western Blot (Recombinant protein) Protocol Download ELISA Gene Information Entrez GeneID: 8239 GeneBank NM_021906 Accession#: Protein NP_068706 Accession#: Gene Name: USP9X Gene Alias: DFFRX,FAF,FAM Gene ubiquitin specific peptidase 9, X-linked Description: Omim ID: 300072 Gene Ontology: Hyperlink Gene Summary: This gene is a member of the peptidase C19 family and encodes a protein that is similar to ubiquitin-specific proteases. Though this gene is located on the X chromosome, it escapes X-inactivation. Mutations in this gene have been associated with Turner syndrome. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. -
Characterizing Genomic Duplication in Autism Spectrum Disorder by Edward James Higginbotham a Thesis Submitted in Conformity
Characterizing Genomic Duplication in Autism Spectrum Disorder by Edward James Higginbotham A thesis submitted in conformity with the requirements for the degree of Master of Science Graduate Department of Molecular Genetics University of Toronto © Copyright by Edward James Higginbotham 2020 i Abstract Characterizing Genomic Duplication in Autism Spectrum Disorder Edward James Higginbotham Master of Science Graduate Department of Molecular Genetics University of Toronto 2020 Duplication, the gain of additional copies of genomic material relative to its ancestral diploid state is yet to achieve full appreciation for its role in human traits and disease. Challenges include accurately genotyping, annotating, and characterizing the properties of duplications, and resolving duplication mechanisms. Whole genome sequencing, in principle, should enable accurate detection of duplications in a single experiment. This thesis makes use of the technology to catalogue disease relevant duplications in the genomes of 2,739 individuals with Autism Spectrum Disorder (ASD) who enrolled in the Autism Speaks MSSNG Project. Fine-mapping the breakpoint junctions of 259 ASD-relevant duplications identified 34 (13.1%) variants with complex genomic structures as well as tandem (193/259, 74.5%) and NAHR- mediated (6/259, 2.3%) duplications. As whole genome sequencing-based studies expand in scale and reach, a continued focus on generating high-quality, standardized duplication data will be prerequisite to addressing their associated biological mechanisms. ii Acknowledgements I thank Dr. Stephen Scherer for his leadership par excellence, his generosity, and for giving me a chance. I am grateful for his investment and the opportunities afforded me, from which I have learned and benefited. I would next thank Drs. -
Post-Translational Modifications of the Energy Guardian AMP-Activated
International Journal of Molecular Sciences Review Post-Translational Modifications of the Energy Guardian AMP-Activated Protein Kinase Ashley J. Ovens 1,2 , John W. Scott 2,3,4 , Christopher G. Langendorf 3, Bruce E. Kemp 2,3, Jonathan S. Oakhill 1,2 and William J. Smiles 1,* 1 Metabolic Signalling Laboratory, St Vincent’s Institute of Medical Research, School of Medicine, University of Melbourne, Fitzroy, VIC 3065, Australia; [email protected] (A.J.O.); [email protected] (J.S.O.) 2 Mary MacKillop Institute for Health Research, Australian Catholic University, Fitzroy, VIC 3000, Australia; [email protected] (J.W.S.); [email protected] (B.E.K.) 3 Protein Chemistry & Metabolism, St Vincent’s Institute of Medical Research, School of Medicine, University of Melbourne, Fitzroy, VIC 3065, Australia; [email protected] 4 The Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3052, Australia * Correspondence: [email protected] Abstract: Physical exercise elicits physiological metabolic perturbations such as energetic and ox- idative stress; however, a diverse range of cellular processes are stimulated in response to combat these challenges and maintain cellular energy homeostasis. AMP-activated protein kinase (AMPK) is a highly conserved enzyme that acts as a metabolic fuel sensor and is central to this adaptive response to exercise. The complexity of AMPK’s role in modulating a range of cellular signalling cascades is well documented, yet aside from its well-characterised regulation by activation loop phosphorylation, AMPK is further subject to a multitude of additional regulatory stimuli. There- fore, in this review we comprehensively outline current knowledge around the post-translational Citation: Ovens, A.J; Scott, J.W; modifications of AMPK, including novel phosphorylation sites, as well as underappreciated roles for Langendorf, C.G; Kemp, B.E; Oakhill, ubiquitination, sumoylation, acetylation, methylation and oxidation. -
Rabbit Anti-AZI1/FITC Conjugated Antibody-SL12977R-FITC
SunLong Biotech Co.,LTD Tel: 0086-571- 56623320 Fax:0086-571- 56623318 E-mail:[email protected] www.sunlongbiotech.com Rabbit Anti-AZI1/FITC Conjugated antibody SL12977R-FITC Product Name: Anti-AZI1/FITC Chinese Name: FITC标记的中心体蛋白AZI1抗体 5 azacytidine induced 1; 5-azacytidine induced 1; 5-azacytidine-induced protein 1; AZ1; Azi; Azi1; AZI1_HUMAN; Centrosomal protein 131 kDa; Centrosomal protein of 131 Alias: kDa; Centrosomal protein of 131 kDa; Cep131; Cep131; KIAA1118; OTTMUSP00000004498; Pre-acrosome localization protein 1; RP23 37J21.1. Organism Species: Rabbit Clonality: Polyclonal React Species: Human,Mouse,Rat,Chicken,Pig,Cow,Horse,Sheep, ICC=1:50-200IF=1:50-200 Applications: not yet tested in other applications. optimal dilutions/concentrations should be determined by the end user. Molecular weight: 122kDa Form: Lyophilized or Liquid Concentration: 1mg/ml immunogen: KLH conjugated synthetic peptide derived from human AZI1 Lsotype: IgG Purification: affinitywww.sunlongbiotech.com purified by Protein A Storage Buffer: 0.01M TBS(pH7.4) with 1% BSA, 0.03% Proclin300 and 50% Glycerol. Store at -20 °C for one year. Avoid repeated freeze/thaw cycles. The lyophilized antibody is stable at room temperature for at least one month and for greater than a year Storage: when kept at -20°C. When reconstituted in sterile pH 7.4 0.01M PBS or diluent of antibody the antibody is stable for at least two weeks at 2-4 °C. background: AZI1 is a 1,083 amino acid protein that may play a role in spermatogenesis. AZI1 is most highly expressed in spinal cord, followed by testis, ovary, amygdala, cerebellum Product Detail: and thalamus. -
GILZ-Dependent Modulation of Mtorc1 Regulates Spermatogonial Maintenance Hue M
© 2018. Published by The Company of Biologists Ltd | Development (2018) 145, dev165324. doi:10.1242/dev.165324 STEM CELLS AND REGENERATION RESEARCH ARTICLE GILZ-dependent modulation of mTORC1 regulates spermatogonial maintenance Hue M. La1,2,*, Ai-Leen Chan1,2,*, Julien M. D. Legrand1,2, Fernando J. Rossello1,2, Christina G. Gangemi1,2, Antonella Papa3, Qiang Cheng4, Eric F. Morand4 and Robin M. Hobbs1,2,‡ ABSTRACT prospermatogonia) upon migration to the basement membrane of Male fertility is dependent on spermatogonial stem cells (SSCs) that the seminiferous cords. The undifferentiated population contains self-renew and produce differentiating germ cells. Growth factors isolated spermatogonia (A-single or As) plus chains of cells produced within the testis are essential for SSC maintenance interconnected by cytoplasmic bridges. Two-cell chains are but intrinsic factors that dictate the SSC response to these stimuli known as A-paired (Apr) whereas chains of four or more cells are poorly characterised. Here, we have studied the role of GILZ, are known as A-aligned (Aal). Lineage-tracing studies demonstrate α a TSC22D family protein and spermatogenesis regulator, in that SSCs are marked by GFR 1 and typically As and Apr,whereas spermatogonial function and signalling. Although broadly expressed most undifferentiated cells, particularly Aal, are committed in the germline, GILZ was prominent in undifferentiated spermatogonia progenitors and marked by NGN3 (Hara et al., 2014; Nakagawa + and Gilz deletion in adults resulted in exhaustion of the GFRα1+ et al., 2010). NGN3 Aal may revert to SSCs through chain SSC-containing population and germline degeneration. GILZ loss fragmentation, particularly upon tissue damage (Nakagawa et al., γ was associated with mTORC1 activation, suggesting enhanced 2010). -
The SON RNA Splicing Factor Is Required for Intracellular Trafficking That Promotes Centriole Assembly
bioRxiv preprint doi: https://doi.org/10.1101/2021.01.29.428802; this version posted January 29, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. SON is required for centriole assembly. 1 2 The SON RNA splicing factor is required for intracellular trafficking that 3 promotes centriole assembly. 4 5 6 Alexander J. Stemm-Wolf1, Eileen T. O’Toole2, Ryan M. Sheridan3, Jacob T. Morgan1, and Chad 7 G. Pearson1* 8 9 1 Department of Cell and Developmental Biology, University of Colorado – Anschutz Medical 10 Campus, Aurora CO 80045 11 2 MCDB, University of Colorado – Boulder, Boulder, CO 12 3 RNA Biosciences Initiative (RBI), University of Colorado – Anschutz Medical Campus, Aurora 13 CO 80045 14 15 * Correspondence: [email protected] 16 17 18 19 KEYWORDS: Centrosome, centriole, centriolar satellite, alternative splicing 20 ABBREVIATIONS: MTOC – microtubule organizing center, SIM – structured illumination 21 microscopy, EM – electron microscopy 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.01.29.428802; this version posted January 29, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. SON is required for centriole assembly. 22 Abstract 23 Control of centrosome assembly is critical for cell division, intracellular trafficking and cilia.