DOCSLIB.ORG

(12) Patent Application Publication (10) Pub. No.: US 2009/0227533 A1 Bader Et Al

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(12) Patent Application Publication (10) Pub. No.: US 2009/0227533 A1 Bader Et Al US 20090227533A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0227533 A1 Bader et al. (43) Pub. Date: Sep. 10, 2009 (54) MIR-34 REGULATED GENES AND Related U.S. Application Data PATHWAYS AS TARGETS FOR THERAPEUTIC INTERVENTION (60) Provisional application No. 60/942.971, filed on Jun. 8, 2007. (76) Inventors: Andreas G. Bader, Austin, TX Publication Classification (US); Lubna Patrawala, Austin, TX (US); Jason F. Wiggins, Austin, (51) Int. Cl. TX (US); Mike W. Byrom, Austin, A 6LX 3L/705 (2006.01) TX (US); Charles D. Johnson, CI2N 5/06 (2006.01) Austin, TX (US); David Brown, GOIN 33/50 (2006.01) Austin, TX (US) CI2O I/68 (2006.01) A6IP35/00 (2006.01) Correspondence Address: (52) U.S. Cl. .................. 514/44; 435/375; 436/94; 435/6 Fulbright & Jaworski L.L.P. 600 Congress Avenue, Suite 2400 (57) ABSTRACT Austin, TX 78701 (US) The present invention concerns methods and compositions for identifying genes or genetic pathways modulated by miR (21) Appl. No.: 12/134,932 34, using miR-34 to modulate a gene or gene pathway, using this profile in assessing the condition of a patient and/or (22) Filed: Jun. 6, 2008 treating the patient with an appropriate miRNA. 160 140 A549 H460 H522 : H596 is H1650 Calu-3 %, H226 SHCC2935 5 120 100 %Š GO %2 %.S. 60 SS %& Š ÉS 40 %.S. Š &%Š 20 3 3. Patent Application Publication Sep. 10, 2009 Sheet 1 of 9 US 2009/0227533 A1 s: C O O. O. O. O. O. O. v (N C CO CO w CN 3 w v. v uOeuego. 9 Patent Application Publication Sep. 10, 2009 Sheet 2 of 9 US 2009/0227533 A1 s C CD i E s w c SD ld O O O. O. O. O. O O O D O N LO CN : s wres Ol. x) equinu IIeo Patent Application Publication Sep. 10, 2009 Sheet 3 of 9 US 2009/0227533 A1 2 2 Ks s i uolelejo. Patent Application Publication Sep. 10, 2009 Sheet 4 of 9 US 2009/0227533 A1 9202/|17?89 uo?e?noou??sodsÁed Z 009 007 009 00Z 00|| (uu) ez's Jouni Patent Application Publication Sep. 10, 2009 Sheet 5 of 9 US 2009/0227533 A1 CN 3. 2. Y s w E3:3: D (5 vs. L O % Z & % O O O O O O O N. O. CO CO w CN 3 s ve ve uOelejo. 9 Patent Application Publication US 2009/0227533 A1 Patent Application Publication Sep ... 10, 2009 Sheet 8 of 9 US 2009/0227533 A1 Patent Application Publication Sep. 10, 2009 Sheet 9 of 9 US 2009/0227533 A1 SON seo US 2009/0227533 A1 Sep. 10, 2009 MR-34 REGULATED GENES AND cells (22Rv1), lung cancer cells (A549), basal cell carcinoma PATHWAYS AS TARGETS FOR cells (TE354T), cervical cancer cells (HeLa), and leukemic T THERAPEUTIC INTERVENTION cells (Jurkat), but miR-34a had no anti-proliferative effect on normal human T cells. Upon transformation, miR-34a increased (Jurkat) or decreased (HeLa) programmed cell 0001. This application claims priority to U.S. Provisional death (apoptosis) in cells. Uncontrolled cell proliferation is a Application Ser. No. 60/942,971 filed Jun. 8, 2007, which is hallmark of cancer. Apoptosis is a natural cellular process that incorporated herein by reference in its entirety. helps control cancer by inducing death in cells with onco genic potential. Many oncogenes function by altering induc BACKGROUND OF THE INVENTION tion of apoptosis. More recently, others have observed miR 0002 I. Field of the Invention 34a to be over-expressed in cancerous liver cells (Meng et al., 0003. The present invention relates to the fields of molecu 2006). lar biology and medicine. More specifically, the invention 0009 Bioinformatics analyses suggest that any given relates to methods and compositions for the treatment of miRNA may bind to and alter the expression of up to several diseases or conditions that are affected by miR-34 microR hundred different genes. In addition, a single gene may be NAS, microRNA expression, and genes and cellular pathways regulated by several miRNAs. Thus, each miRNA may regu directly and indirectly modulated by such. late a complex interaction among genes, gene pathways, and 0004 II. Background gene networks. Mis-regulation or alteration of these regula 0005. In 2001, several groups used a cloning method to tory pathways and networks, involving miRNAS, are likely to isolate and identify a large group of “microRNAs (miRNAs) contribute to the development of disorders and diseases such from C. elegans, Drosophila, and humans (Lagos-Quintana et as cancer. Although bioinformatics tools are helpful in pre al., 2001; Lau et al., 2001; Lee and Ambros, 2001). Several dicting miRNA binding targets, all have limitations. Because hundreds of miRNAs have been identified in plants and ani of the imperfect complementarity with their target binding mals—including humans—which do not appear to have sites, it is difficult to accurately predict the mRNA targets of endogenous siRNAs. Thus, while similar to siRNAs, miR miRNAs with bioinformatics tools alone. Furthermore, the NAS are distinct. complicated interactive regulatory networks among miRNAS 0006 miRNAs thus far observed have been approximately and target genes make it difficult to accurately predict which 21-22 nucleotides in length, and they arise from longer pre genes will actually be mis-regulated in response to a given cursors, which are transcribed from non-protein-encoding miRNA. genes. See review of Carrington and Ambros (2003). The 0010 Correcting gene expression errors by manipulating precursors form structures that fold back on themselves in miRNA expression or by repairing miRNA mis-regulation self-complementary regions; they are then processed by the represent promising methods to repair genetic disorders and nuclease Dicer (in animals) or DCL1 (in plants) to generate cure diseases like cancer. A current, disabling limitation of the short double-stranded miRNA. One of the miRNA strands this approach is that, as mentioned above, the details of the is incorporated into a complex of proteins and miRNA called regulatory pathways and networks that are affected by any the RNA-induced silencing complex. The miRNA guides the given miRNA, including miR-34, remain largely unknown. RISC complex to a target mRNA, which is then cleaved or This represents a significant limitation for treatment of can translationally silenced, depending on the degree of sequence cers in which miR-34 may play a role. A need exists to complementarity of the miRNA to its target mRNA. Cur identify the genes, genetic pathways, and genetic networks rently, it is believed that perfect or nearly perfect complemen that are regulated by or that may regulate hsa-miR-34 expres tarity leads to mRNA degradation, as is most commonly S1O. observed in plants. In contrast, imperfect base pairing, as is primarily found in animals, leads to translational silencing. SUMMARY OF THE INVENTION However, recent data Suggest additional complexity (Bagga 0011. The present invention provides additional composi et al., 2005; Lim et al., 2005), and mechanisms of gene tions and methods by identifying genes that are direct targets silencing by miRNAS remain under intense study. for miR-34 regulation or that are indirect or downstream 0007 Recent studies have shown that changes in the targets of regulation following the miR-34-mediated modifi expression levels of numerous miRNAs are associated with cation of another gene(s) expression. Furthermore, the inven various cancers (reviewed in Esquela-Kerscher and Slack, tion describes gene, disease, and/or physiologic pathways 2006; Calin and Croce, 2006). miRNAs have also been impli and networks that are influenced by miR-34 and its family cated in regulating cell growth and cell and tissue differen members. In certain aspects, compositions of the invention tiation—cellular processes that are associated with the devel are administered to a Subject having, Suspected of having, or opment of cancer. at risk of developing a metabolic, an immunologic, an infec 0008. The inventors previously demonstrated that hsa tious, a cardiovascular, a digestive, an endocrine, an ocular, a miR-34 is involved with the regulation of numerous cell genitourinary, a blood, a musculoskeletal, a nervous system, activities that represent intervention points for cancer therapy a congenital, a respiratory, a skin, or a cancerous disease or and for therapy of other diseases and disorders (U.S. patent condition. application Ser. No. 1 1/141,707 filed May 31, 2005 and Ser. 0012. In particular aspects, a subject or patient may be No. 1 1/273,640 filed Nov. 14, 2005, each of which is incor selected for treatment based on expression and/or aberrant porated herein by reference in its entirety). In a survey of 24 expression of one or more miRNA or mRNA. In a further different humantissues, the inventors observed that miR-34 is aspect, a subject or patient may be selected for treatment preferentially or exclusively expressed in human lymph node based on aberrations in one or more biologic or physiologic tissues. When transformed into various cancer cell lines from pathway(s), including aberrant expression of one or more humans, miR-34a inhibits the proliferation of prostate cancer gene associated with a pathway, or the aberrant expression of US 2009/0227533 A1 Sep. 10, 2009 one or more protein encoded by one or more gene associated cervical, a uterine, a brain, a neuronal, a blood, a cervical, an with a pathway. In still a further aspect, a Subject or patient esophageal, a lung, a cardiovascular, a liver, a breast, a bone, may be selected based on aberrations in miRNA expression, a thyroid, a glandular, an adrenal, a pancreatic, a stomach, a or biologic and/or physiologic pathway(s).
Load more

Recommended publications
  • New Concepts in Basement Membrane Biology Willi Halfter1, Philipp Oertle2, Christophe A
    REVIEW ARTICLE New concepts in basement membrane biology Willi Halfter1, Philipp Oertle2, Christophe A. Monnier2,*, Leon Camenzind2, Magaly Reyes-Lua1, Huaiyu Hu3, Joseph Candiello4, Anatalia Labilloy5,†, Manimalha Balasubramani6, Paul Bernhard Henrich1 and Marija Plodinec2,7 1 Department of Ophthalmology, University Hospital Basel, Switzerland 2 Biozentrum and the Swiss Nanoscience Institute, University of Basel, Switzerland 3 Department of Neurobiology and Physiology, Upstate University Hospital, SUNY University, Syracuse, NY, USA 4 Department of Bioengeneering, University of Pittsburgh, PA, USA 5 Department of Renal Physiology, University of Pittsburgh, PA, USA 6 Proteomics Core Facility of the University of Pittsburgh, PA, USA 7 Department of Pathology, University Hospital Basel, Switzerland Keywords Basement membranes (BMs) are thin sheets of extracellular matrix that basal lamina; basement membrane; outline epithelia, muscle fibers, blood vessels and peripheral nerves. The biomechanical properties; collagen IV; current view of BM structure and functions is based mainly on transmis- laminin; membrane asymmetry; nidogen; sion electron microscopy imaging, in vitro protein binding assays, and phe- perlecan notype analysis of human patients, mutant mice and invertebrata. Correspondence Recently, MS-based protein analysis, biomechanical testing and cell adhe- W. Halfter, Department of Ophthalmology, sion assays with in vivo derived BMs have led to new and unexpected University Hospital Basel, Mittlere insights. Proteomic analysis combined with ultrastructural studies showed Strasse 91, 4031 Basel, Switzerland that many BMs undergo compositional and structural changes with Fax: +41 61 267 21 09 advancing age. Atomic force microscopy measurements in combination Tel: +49 7624 982528 with phenotype analysis have revealed an altered mechanical stiffness that E-mail: [email protected] M.
    [Show full text]
  • Molecular and Physiological Basis for Hair Loss in Near Naked Hairless and Oak Ridge Rhino-Like Mouse Models: Tracking the Role of the Hairless Gene
    University of Tennessee, Knoxville TRACE: Tennessee Research and Creative Exchange Doctoral Dissertations Graduate School 5-2006 Molecular and Physiological Basis for Hair Loss in Near Naked Hairless and Oak Ridge Rhino-like Mouse Models: Tracking the Role of the Hairless Gene Yutao Liu University of Tennessee - Knoxville Follow this and additional works at: https://trace.tennessee.edu/utk_graddiss Part of the Life Sciences Commons Recommended Citation Liu, Yutao, "Molecular and Physiological Basis for Hair Loss in Near Naked Hairless and Oak Ridge Rhino- like Mouse Models: Tracking the Role of the Hairless Gene. " PhD diss., University of Tennessee, 2006. https://trace.tennessee.edu/utk_graddiss/1824 This Dissertation is brought to you for free and open access by the Graduate School at TRACE: Tennessee Research and Creative Exchange. It has been accepted for inclusion in Doctoral Dissertations by an authorized administrator of TRACE: Tennessee Research and Creative Exchange. For more information, please contact [email protected]. To the Graduate Council: I am submitting herewith a dissertation written by Yutao Liu entitled "Molecular and Physiological Basis for Hair Loss in Near Naked Hairless and Oak Ridge Rhino-like Mouse Models: Tracking the Role of the Hairless Gene." I have examined the final electronic copy of this dissertation for form and content and recommend that it be accepted in partial fulfillment of the requirements for the degree of Doctor of Philosophy, with a major in Life Sciences. Brynn H. Voy, Major Professor We have read this dissertation and recommend its acceptance: Naima Moustaid-Moussa, Yisong Wang, Rogert Hettich Accepted for the Council: Carolyn R.
    [Show full text]
  • Ophthalmological Features Associated with COL4A1 Mutations
    OPHTHALMIC MOLECULAR GENETICS SECTION EDITOR: JANEY L. WIGGS, MD, PhD Ophthalmological Features Associated With COL4A1 Mutations Isabelle Coupry, PhD; Igor Sibon, MD, PhD; Bruno Mortemousque, MD; Franc¸ois Rouanet, MD; Manuele Mine, PharmD, PhD; Cyril Goizet, MD, PhD Objective: To investigate the wide variability of ocular Conclusions: The COL4A1 mutations may be associ- manifestations associated with mutations in the COL4A1 ated with various ophthalmologic developmental anoma- gene that encodes collagen IV␣1. lies of anterior segment dysgenesis type, which are reminiscent of Axenfeld-Rieger anomalies (ARA). Cere- Methods: We clinically evaluated 7 patients from 2 un- brovascular disorders should be added to the list of signs related families in whom ocular features segregated with potentially associated with ARA. COL4A1 mutations that were identified by direct se- quencing. Clinical Relevance: These data suggest that cerebral magnetic resonance imaging may be recommended in Results: The G2159A transition (c.2159GϾA) that leads the clinical treatment of patients with apparently iso- tothemissensemutationp.Gly720Aspwasidentifiedinfam- lated ARA, even when neurological symptoms or signs ily A. An ocular phenotype of variable severity was observed are lacking. in all affected relatives. The missense mutation c.2263GϾA, p.Gly755Arg was identified in family B. One patient from family B also displayed notable ocular features. Arch Ophthalmol. 2010;128(4):483-489 NEW FORM OF HEREDITARY constellation of ocular findings that in- cerebrovascular disorder clude anomalies of the anterior chamber was recently associated angle and aqueous drainage structures (iri- with mutations in the dogoniodysgenesis), iris hypoplasia, ec- COL4A1 gene that en- centric pupil (corectopia), iris tears (poly- Acodes collagen IV␣1.1,2 Mutations in coria), and iridocorneal adhesions COL4A1 were initially associated with ce- traversing the anterior chamber.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Studies on the Proteome of Human Hair - Identifcation of Histones and Deamidated Keratins Received: 15 August 2017 Sunil S
    www.nature.com/scientificreports OPEN Studies on the Proteome of Human Hair - Identifcation of Histones and Deamidated Keratins Received: 15 August 2017 Sunil S. Adav 1, Roopa S. Subbaiaih2, Swat Kim Kerk 2, Amelia Yilin Lee 2,3, Hui Ying Lai3,4, Accepted: 12 January 2018 Kee Woei Ng3,4,7, Siu Kwan Sze 1 & Artur Schmidtchen2,5,6 Published: xx xx xxxx Human hair is laminar-fbrous tissue and an evolutionarily old keratinization product of follicle trichocytes. Studies on the hair proteome can give new insights into hair function and lead to the development of novel biomarkers for hair in health and disease. Human hair proteins were extracted by detergent and detergent-free techniques. We adopted a shotgun proteomics approach, which demonstrated a large extractability and variety of hair proteins after detergent extraction. We found an enrichment of keratin, keratin-associated proteins (KAPs), and intermediate flament proteins, which were part of protein networks associated with response to stress, innate immunity, epidermis development, and the hair cycle. Our analysis also revealed a signifcant deamidation of keratin type I and II, and KAPs. The hair shafts were found to contain several types of histones, which are well known to exert antimicrobial activity. Analysis of the hair proteome, particularly its composition, protein abundances, deamidated hair proteins, and modifcation sites, may ofer a novel approach to explore potential biomarkers of hair health quality, hair diseases, and aging. Hair is an important and evolutionarily conserved structure. It originates from hair follicles deep within the der- mis and is mainly composed of hair keratins and KAPs, which form a complex network that contributes to the rigidity and mechanical properties.
    [Show full text]
  • To Study Mutant P53 Gain of Function, Various Tumor-Derived P53 Mutants
    Differential effects of mutant TAp63γ on transactivation of p53 and/or p63 responsive genes and their effects on global gene expression. A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science By Shama K Khokhar M.Sc., Bilaspur University, 2004 B.Sc., Bhopal University, 2002 2007 1 COPYRIGHT SHAMA K KHOKHAR 2007 2 WRIGHT STATE UNIVERSITY SCHOOL OF GRADUATE STUDIES Date of Defense: 12-03-07 I HEREBY RECOMMEND THAT THE THESIS PREPARED UNDER MY SUPERVISION BY SHAMA KHAN KHOKHAR ENTITLED Differential effects of mutant TAp63γ on transactivation of p53 and/or p63 responsive genes and their effects on global gene expression BE ACCEPTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF Master of Science Madhavi P. Kadakia, Ph.D. Thesis Director Daniel Organisciak , Ph.D. Department Chair Committee on Final Examination Madhavi P. Kadakia, Ph.D. Steven J. Berberich, Ph.D. Michael Leffak, Ph.D. Joseph F. Thomas, Jr., Ph.D. Dean, School of Graduate Studies 3 Abstract Khokhar, Shama K. M.S., Department of Biochemistry and Molecular Biology, Wright State University, 2007 Differential effect of TAp63γ mutants on transactivation of p53 and/or p63 responsive genes and their effects on global gene expression. p63, a member of the p53 gene family, known to play a role in development, has more recently also been implicated in cancer progression. Mice lacking p63 exhibit severe developmental defects such as limb truncations, abnormal skin, and absence of hair follicles, teeth, and mammary glands. Germline missense mutations of p63 have been shown to be responsible for several human developmental syndromes including SHFM, EEC and ADULT syndromes and are associated with anomalies in the development of organs of epithelial origin.
    [Show full text]
  • UNIVERSITY of CALIFORNIA, IRVINE Combinatorial Regulation By
    UNIVERSITY OF CALIFORNIA, IRVINE Combinatorial regulation by maternal transcription factors during activation of the endoderm gene regulatory network DISSERTATION submitted in partial satisfaction of the requirements for the degree of DOCTOR OF PHILOSOPHY in Biological Sciences by Kitt D. Paraiso Dissertation Committee: Professor Ken W.Y. Cho, Chair Associate Professor Olivier Cinquin Professor Thomas Schilling 2018 Chapter 4 © 2017 Elsevier Ltd. © 2018 Kitt D. Paraiso DEDICATION To the incredibly intelligent and talented people, who in one way or another, helped complete this thesis. ii TABLE OF CONTENTS Page LIST OF FIGURES vii LIST OF TABLES ix LIST OF ABBREVIATIONS X ACKNOWLEDGEMENTS xi CURRICULUM VITAE xii ABSTRACT OF THE DISSERTATION xiv CHAPTER 1: Maternal transcription factors during early endoderm formation in 1 Xenopus Transcription factors co-regulate in a cell type-specific manner 2 Otx1 is expressed in a variety of cell lineages 4 Maternal otx1 in the endodermal conteXt 5 Establishment of enhancers by maternal transcription factors 9 Uncovering the endodermal gene regulatory network 12 Zygotic genome activation and temporal control of gene eXpression 14 The role of maternal transcription factors in early development 18 References 19 CHAPTER 2: Assembly of maternal transcription factors initiates the emergence 26 of tissue-specific zygotic cis-regulatory regions Introduction 28 Identification of maternal vegetally-localized transcription factors 31 Vegt and OtX1 combinatorially regulate the endodermal 33 transcriptome iii
    [Show full text]
  • A Collagen Glucosyltransferase Drives Lung Adenocarcinoma Progression in Mice
    ARTICLE https://doi.org/10.1038/s42003-021-01982-w OPEN A collagen glucosyltransferase drives lung adenocarcinoma progression in mice Hou-Fu Guo 1, Neus Bota-Rabassedas 1, Masahiko Terajima 2, B. Leticia Rodriguez1, Don L. Gibbons 1, Yulong Chen1, Priyam Banerjee1, Chi-Lin Tsai 3, Xiaochao Tan1, Xin Liu1, Jiang Yu1, Michal Tokmina-Roszyk4, Roma Stawikowska4, Gregg B. Fields4, Mitchell D. Miller 5, Xiaoyan Wang3, Juhoon Lee6,7, Kevin N. Dalby6,7, Chad J. Creighton 8,9, George N. Phillips Jr 5,10, John A. Tainer 3, Mitsuo Yamauchi2 & ✉ Jonathan M. Kurie 1 Cancer cells are a major source of enzymes that modify collagen to create a stiff, fibrotic tumor stroma. High collagen lysyl hydroxylase 2 (LH2) expression promotes metastasis and 1234567890():,; is correlated with shorter survival in lung adenocarcinoma (LUAD) and other tumor types. LH2 hydroxylates lysine (Lys) residues on fibrillar collagen’s amino- and carboxy-terminal telopeptides to create stable collagen cross-links. Here, we show that electrostatic interac- tions between the LH domain active site and collagen determine the unique telopeptidyl lysyl hydroxylase (tLH) activity of LH2. However, CRISPR/Cas-9-mediated inactivation of tLH activity does not fully recapitulate the inhibitory effect of LH2 knock out on LUAD growth and metastasis in mice, suggesting that LH2 drives LUAD progression, in part, through a tLH- independent mechanism. Protein homology modeling and biochemical studies identify an LH2 isoform (LH2b) that has previously undetected collagen galactosylhydroxylysyl glucosyl- transferase (GGT) activity determined by a loop that enhances UDP-glucose-binding in the GLT active site and is encoded by alternatively spliced exon 13 A.
    [Show full text]
  • Genome-Scale Identification of Transcription Factors That Mediate An
    ARTICLE DOI: 10.1038/s41467-018-04406-2 OPEN Genome-scale identification of transcription factors that mediate an inflammatory network during breast cellular transformation Zhe Ji 1,2,4, Lizhi He1, Asaf Rotem1,2,5, Andreas Janzer1,6, Christine S. Cheng2,7, Aviv Regev2,3 & Kevin Struhl 1 Transient activation of Src oncoprotein in non-transformed, breast epithelial cells can initiate an epigenetic switch to the stably transformed state via a positive feedback loop that involves 1234567890():,; the inflammatory transcription factors STAT3 and NF-κB. Here, we develop an experimental and computational pipeline that includes 1) a Bayesian network model (AccessTF) that accurately predicts protein-bound DNA sequence motifs based on chromatin accessibility, and 2) a scoring system (TFScore) that rank-orders transcription factors as candidates for being important for a biological process. Genetic experiments validate TFScore and suggest that more than 40 transcription factors contribute to the oncogenic state in this model. Interestingly, individual depletion of several of these factors results in similar transcriptional profiles, indicating that a complex and interconnected transcriptional network promotes a stable oncogenic state. The combined experimental and computational pipeline represents a general approach to comprehensively identify transcriptional regulators important for a biological process. 1 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. 2 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. 3 Department of Biology, Howard Hughes Medical Institute and David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 20140, USA. 4Present address: Department of Pharmacology and Biomedical Engineering, Northwestern University, Evanston 60611 IL, USA.
    [Show full text]
  • FOXK Transcription Factors Regulation and Critical Role in Cancer
    Cancer Letters 458 (2019) 1–12 Contents lists available at ScienceDirect Cancer Letters journal homepage: www.elsevier.com/locate/canlet Mini-review FOXK transcription factors: Regulation and critical role in cancer T Ying Liua, Wei Dingb,HuGea,d, Murugavel Ponnusamya, Qiong Wangd, Xiaodan Haoa, Wei Wua, ∗∗ ∗ Yuan Zhanga, Wanpeng Yua, Xiang Aoa, , Jianxun Wanga,c, a Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China b Department of Comprehensive Internal Medicine, Affiliated Hospital, Qingdao University, Qingdao 266003, China c School of Basic Medical Sciences, Qingdao University, Qingdao 266071, China d Molecular Informatics Department, Hengrui Pharmaceutical Co., Ltd., Shanghai 200245, China ARTICLE INFO ABSTRACT Keywords: Growing evidence suggests that alterations of gene expression including expression and activities of transcription FOXK1 factors are closely associated with carcinogenesis. Forkhead Box Class K (FOXK) proteins, FOXK1 and FOXK2, FOXK2 are a family of evolutionarily conserved transcriptional factors, which have recently been recognized as key ncRNAs transcriptional regulators involved in many types of cancer. Members of the FOXK family mediate a wide Biomarker spectrum of biological processes, including cell proliferation, differentiation, apoptosis, autophagy, cell cycle Therapeutic target progression, DNA damage and tumorigenesis. Therefore, the deregulation of FOXKs can affect the cell fate and they promote tumorigenesis as well as cancer progression. The mechanisms of FOXKs regulation including post- translational modifications (PTMs), microRNAs (miRNAs) and protein–protein interactions are well demon- strated. However, the detailed mechanisms of FOXKs activation and deregulation in cancer progression are still inconclusive. In this review, we summarize the regulatory mechanisms of FOXKs expression and activity, and their role in the development and progression of cancer.
    [Show full text]
  • Collagen Type XVIII (H-140): Sc-25720
    SANTA CRUZ BIOTECHNOLOGY, INC. Collagen Type XVIII (H-140): sc-25720 The Power to Question BACKGROUND APPLICATIONS Type XV and XVIII collagens form the new subgroup MULTIPLEXIN, within the Collagen Type XVIII (H-140) is recommended for detection of Collagen α1 diverse family of collagens, which contains nineteen distinct types of collagens Type XVIII of mouse, rat and human origin by Western Blotting (starting found in vertebrates. Both type XV and XVIII collagens are characterized by dilution 1:200, dilution range 1:100-1:1000), immunoprecipitation [1–2 µg extensive interruptions in their collagenous sequences. Members of the MUL- per 100–500 µg of total protein (1 ml of cell lysate)] and immunofluores- TIPLEXIN subgroup contain polypeptides with multiple triple-helical domains cence (starting dilution 1:50, dilution range 1:50-1:500). separated and flanked by non-triple-helical regions. Type XV is predominantly Suitable for use as control antibody for Collagen Type XVIII siRNA (h): expressed in internal organs such as adrenal gland, kidney and pancreas. Type sc-43072 and Collagen Type XVIII siRNA (m): sc-43073. XVIII encodes two different α1 chains, which have different signal peptides and variant N-terminal non-collagenous NC1 domains of 495 and 303 amino Molecular Weight of Collagen Type XVIII: 20-22 kDa. acids. The long variant NC1-434 Type XVIII mRNAs are prominently expressed Positive Controls: rat C6 glioblastoma, human PBL or rat lung extract: sc-2396. in liver, while the variant NC1-303 mRNAs are predominantly expressed in heart, kidney, placenta, prostate, ovaries, skeletal muscle and small intestine. RECOMMENDED SECONDARY REAGENTS Endostatin is a fragment of the C-terminal domain NC1 of collagen XV and XVIII that inhibits angiogenesis and tumor growth.
    [Show full text]
  • Using Liver Mirna Profiles to Predict Chemical Hepatocarcinogenesis”
    “Using liver miRNA profiles to predict chemical hepatocarcinogenesis” By Costas Koufaris A thesis submitted to Imperial College London for the degree of Doctor of Philosophy Department of Surgery and Cancer Biomolecular Medicine Imperial College London April- 12011 - ABSTRACT Industrial, agricultural, and pharmaceutical requirements drive the development of a plethora of new chemical entities each year, many of which -for example drugs, pesticides, and food additives- have to be assessed for potential human health hazard. The current benchmark for risk assessement is the lifetime rodent bioassay which is expensive, time-consuming, laborious, requires the sacrifice of numerous animals, and is often irrelevant to humans. Hence alternative strategies to the rodent lifetime bioassay for prediction of chemical carcinogens are being pursued, especially for the liver which is an organ frequently affected by exogenous chemicals due to its detoxifying and metabolic roles. Numerous studies in recent years support the important role of microRNAs in cancer development, including hepatocellular carcinoma. The principal hypothesis of this project was that hepatic microRNA signatures can contribute to the earlier prediction of chemical hepatocarcinogens. Examination of livers from male Fischer rats treated with six chemical hepatocarcinogens, with diverse mode of actions for 90 days revealed that all the tested hepatocarcinogens affected the liver miRNAome from that early stage. Interestingly, a small set of microRNAs were identified whose expression
    [Show full text]