DOCSLIB.ORG

Regulation of Serine-Arginine Protein Kinase 1 Functions by Human

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Regulation of Serine-Arginine Protein Kinase 1 Functions by Human REGULATION OF SERINE-ARGININE PROTEIN KINASE 1 FUNCTIONS BY HUMAN PAPILLOMAVIRUS By EMMA LOUISE PRESCOTT A thesis submitted to the University of Birmingham for the degree of DOCTOR OF PHILOSOPHY School of Cancer Sciences College of Medicine and Dentistry University of Birmingham 2011 University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. ABSTRACT The role of the E4 protein in the human papillomavirus (HPV) life cycle is an enigma even though it has varied effects on cell behaviour and organisation in overexpression studies. Full-length E4 proteins are derived from E1^E4 spliced RNA transcripts and E1^E4 proteins from diverse HPV types interact with serine-arginine (SR)-specific protein kinase SRPK1, that regulates diverse cellular functions including RNA splicing. This thesis has sought to address the hypothesis that E1^E4 alters SRPK1 activity and influences SRPK1 functions in the HPV life cycle. This study has uncovered the novel finding that E1^E4 protein of HPV1, but not HPV5, 16 and 18, is a potent inhibitor of SRPK1 activity in vitro and in vivo and inhibition is dependent upon E1^E4 binding to SRPK1. Whilst HPV1 E1^E4 inhibits SRPK1 phosphorylation of cellular (ASF/SF2, SRp20, SC35, 9G8 and SRp75) and viral (HPV E2) SR protein substrates, it has only weak effects on SR protein cellular localisation and on cellular and viral RNA splicing in minigene systems. Addition of the small molecule inhibitor of SRPK, SRPIN340 to organotypic raft cultures of HPV18 genome-containing keratinocytes enhances the morphological features of HPV viral replication suggesting that the HPV may modulate SRPK activity to facilitate the virus life cycle. ACKNOWLEDGEMENTS I would like to thank my supervisor Sally Roberts, for her help and advice throughout my studies. I would also like to thank my previous co-supervisor Ian Bell and past members of the HPV group, especially Craig Delury, for their advice and support. I would like to thank Ben Willcox for his help with the Biacore experiments and all the other people in the School of Cancer Sciences who have given me help and support during the project. Additionally I would like to thank all the good friends I have made during my time in Cancer Sciences, especially the 2007 intake of PhD students, for helping me have fun during my studies and supporting me through the hard times. I would like to thank the College of Medicine and Dentistry for their financial support during my studies and Cancer Research UK for funding the laboratory of Sally Roberts. Finally I thank my family for putting up with me during this stressful time and for believing that I could finish this thesis. Contents CHAPTER 1 GENERAL INTRODUCTION.................................................. 1 1.1 Small DNA tumour viruses ...................................................................................................... 1 1.2 Human papillomavirus ............................................................................................................. 2 1.3 Classification of papillomaviruses ........................................................................................... 2 1.4 Warts and verrucas .................................................................................................................. 5 1.5 Human papillomavirus and cancer ......................................................................................... 6 1.5.1 Non-genital ................................................................................................................................. 6 1.5.2 Anogenital ................................................................................................................................... 9 1.5.3 HPV screening and prophylactic vaccine ................................................................................. 11 1.6 The HPV genome .................................................................................................................... 13 1.7 HPV life cycle .......................................................................................................................... 14 1.7.1 Early virus life cycle ................................................................................................................. 15 1.7.2 Late virus life cycle ................................................................................................................... 17 1.8 Transcriptional control in HPV ............................................................................................. 17 1.8.1 Early promoter control .............................................................................................................. 17 1.8.2 Late promoter control ............................................................................................................... 20 1.9 Post-transcriptional modifications ........................................................................................ 20 1.9.1 Genome splicing ....................................................................................................................... 20 1.9.2 Control of genome splicing ....................................................................................................... 24 1.9.3 Polyadenylation ........................................................................................................................ 25 1.9.4 Translation ................................................................................................................................ 27 1.10 HPV proteins ........................................................................................................................... 27 1.10.1 HPV E1 ..................................................................................................................................... 28 1.10.2 HPV E2 ..................................................................................................................................... 29 1.10.3 HPV E6 protein ......................................................................................................................... 30 1.10.4 HPV E7 ..................................................................................................................................... 33 1.10.5 HPV E5 ..................................................................................................................................... 35 1.10.6 Capsid proteins ......................................................................................................................... 37 1.11 HPV E1^E4 ............................................................................................................................. 38 1.11.1 Post-translational modifications of E4 ...................................................................................... 42 1.11.2 Functions of E1^E4 ................................................................................................................... 43 1.11.2.1 Interaction with structural proteins ........................................................................................... 43 1.11.2.2 Regulation of the cell cycle and cellular DNA synthesis .......................................................... 45 1.11.2.3 Disruption of ND10 bodies ....................................................................................................... 47 1.11.2.4 Induction of apoptosis ............................................................................................................... 48 1.11.2.5 Interaction with components of RNA metabolism .................................................................... 48 1.12 Serine-arginine specific protein kinases ................................................................................ 49 1.13 Serine arginine-rich proteins ................................................................................................. 53 1.13.1 Localisation of SR proteins ....................................................................................................... 54 1.14 Functions of SR proteins ........................................................................................................ 57 1.14.1 pre-mRNA splicing ................................................................................................................... 57 1.14.2 SR protein control of pre-mRNA splicing ................................................................................ 58 Contents 1.14.3 mRNA export, stability and translation .................................................................................... 61 1.14.4 Other functions of SR proteins ................................................................................................. 62 1.14.5 SRPKs, SR proteins and cancer ................................................................................................ 64 1.15 Regulation of SR proteins .....................................................................................................
Load more

Recommended publications
  • 4-6 Weeks Old Female C57BL/6 Mice Obtained from Jackson Labs Were Used for Cell Isolation
    Methods Mice: 4-6 weeks old female C57BL/6 mice obtained from Jackson labs were used for cell isolation. Female Foxp3-IRES-GFP reporter mice (1), backcrossed to B6/C57 background for 10 generations, were used for the isolation of naïve CD4 and naïve CD8 cells for the RNAseq experiments. The mice were housed in pathogen-free animal facility in the La Jolla Institute for Allergy and Immunology and were used according to protocols approved by the Institutional Animal Care and use Committee. Preparation of cells: Subsets of thymocytes were isolated by cell sorting as previously described (2), after cell surface staining using CD4 (GK1.5), CD8 (53-6.7), CD3ε (145- 2C11), CD24 (M1/69) (all from Biolegend). DP cells: CD4+CD8 int/hi; CD4 SP cells: CD4CD3 hi, CD24 int/lo; CD8 SP cells: CD8 int/hi CD4 CD3 hi, CD24 int/lo (Fig S2). Peripheral subsets were isolated after pooling spleen and lymph nodes. T cells were enriched by negative isolation using Dynabeads (Dynabeads untouched mouse T cells, 11413D, Invitrogen). After surface staining for CD4 (GK1.5), CD8 (53-6.7), CD62L (MEL-14), CD25 (PC61) and CD44 (IM7), naïve CD4+CD62L hiCD25-CD44lo and naïve CD8+CD62L hiCD25-CD44lo were obtained by sorting (BD FACS Aria). Additionally, for the RNAseq experiments, CD4 and CD8 naïve cells were isolated by sorting T cells from the Foxp3- IRES-GFP mice: CD4+CD62LhiCD25–CD44lo GFP(FOXP3)– and CD8+CD62LhiCD25– CD44lo GFP(FOXP3)– (antibodies were from Biolegend). In some cases, naïve CD4 cells were cultured in vitro under Th1 or Th2 polarizing conditions (3, 4).
    [Show full text]
  • Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
    Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase
    [Show full text]
  • The RNA-Binding Protein ESRP1 Modulates the Expression of Rac1b in Colorectal Cancer Cells
    cancers Article The RNA-Binding Protein ESRP1 Modulates the Expression of RAC1b in Colorectal Cancer Cells Marta Manco 1,†, Ugo Ala 2,† , Daniela Cantarella 3, Emanuela Tolosano 1 , Enzo Medico 3 , Fiorella Altruda 2,* and Sharmila Fagoonee 4,* 1 Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy; [email protected] (M.M.); [email protected] (E.T.) 2 Department of Veterinary Science, University of Turin, Largo Paolo Braccini 2, 10095 Grugliasco, Italy; [email protected] 3 Department of Oncology, University of Torino, S.P. 142, km 3.95, Torino, 10060 Candiolo, Italy; [email protected] (D.C.); [email protected] (E.M.) 4 Institute of Biostructure and Bioimaging, National Research Council (CNR) c/o Molecular Biotechnology Center, 10126 Turin, Italy * Correspondence: fi[email protected] (F.A.); [email protected] or [email protected] (S.F.) † These authors contributed equally to this work. Simple Summary: Colorectal cancer (CRC) ranks third for incidence and second for number of deaths among cancer types worldwide. Poor patient survival due to inadequate response to currently available treatment regimens points to the urgent requirement for personalized therapy in CRC patients. Our aim was to provide mechanistic insights into the pro-tumorigenic role of the RNA- binding protein ESRP1, which is highly expressed in a subset of CRC patients. We show that, in CRC cells, ESRP1 binds to and has the same trend in expression as RAC1b, a well-known tumor promoter. Citation: Manco, M.; Ala, U.; Thus, RAC1b may be a potential therapeutic target in ESRP1-overexpressing CRC.
    [Show full text]
  • Thesis Written by Shorog Al Omair B.S., University of Dmmam, 2010 M.S
    Thesis written by Shorog Al Omair B.S., University of Dmmam, 2010 M.S., Kent State University, 2015 Approved by Gail Fraizer, Associate Professor, Ph.D., Masters Advisor, School of Biomedical Sciences Ernest J. Freeman, Ph.D., Director, School of Biomedical Sciences James BlanK, Ph.D., Dean, College of Arts and Sciences Regulators of VEGF-a major isoforms in leukemia A thesis submitted To Kent State University in partial Fulfillment of the requirements for the Degree of Master of Science by Shorog Al Omair July 2015 © Copyright All rights reserved Except for previously published materials TABLE OF CONTENTS TABLE OF CONTENTS………………………………………………………………………………….… iii LIST OF FIGURES……………………………………………………………………………...………….… iv LIST OF TABLES……………………………………………………………………………………………… v LIST OF ABBREVIATIONS…………………………………………………………………………….… vi ACKNOWLEDGMENTS………………….………………………………………………...………...….. viii I. INTRODUCTION…………………………………………………………………….………1 II. METHODOLOGY………………………………………………………….…………… 24 III. RESULTS…………………..………………………………………………………………29 IV. DISCUSSION……………...………………………………………………....….………..45 V. FUTURE DIRECTIONS……………......………………...………………..………….52 VI. REFERENCES……………...……………………………...………………..….…….….55 iii LIST OF FIGURES Figure 1. Alternative splicing regulatory sequences and splicing factors………......….7 Figure 2. The SR proteins shuttle between the cytoplasm and the nucleus……………12 Figure 3. WT1 structure.…………….….….……………………………………………………….....….14 Figure 4. Major VEGF-a isoforms.…………….….….…..……….………………....……………..….18 Figure 5. Characterization of VEGF-a major
    [Show full text]
  • (B6;129.Cg-Gt(ROSA)26Sor Tm20(CAG-Ctgf-GFP)Jsd) Were Crossed with Female Foxd1cre/+ Heterozygote Mice 1, and Experimental Mice Were Selected As Foxd1cre/+; Rs26cig/+
    Supplemental Information SI Methods Animal studies Heterozygote mice (B6;129.Cg-Gt(ROSA)26Sor tm20(CAG-Ctgf-GFP)Jsd) were crossed with female Foxd1Cre/+ heterozygote mice 1, and experimental mice were selected as Foxd1Cre/+; Rs26CIG/+. In some studies Coll-GFPTg or TCF/Lef:H2B-GFPTg mice or Foxd1Cre/+; Rs26tdTomatoR/+ mice were used as described 2; 3. Left kidneys were subjected to ureteral obstruction using a posterior surgical approach as described 2. In some experiments recombinant mouse DKK1 (0.5mg/kg) or an equal volume of vehicle was administered by daily IP injection. In the in vivo ASO experiment, either specific Lrp6 (TACCTCAATGCGATTT) or scrambled negative control ASO (AACACGTCTATACGC) (30mg/kg) (Exiqon, LNA gapmers) was administered by IP injection on d-1, d1, d4, and d7. In other experiments anti-CTGF domain-IV antibodies (5mg/kg) or control IgG were administered d-1, d1 and d6. All animal experiments were performed under approved IACUC protocols held at the University of Washington and Biogen. Recombinant protein and antibody generation and characterization Human CTGF domain I (sequence Met1 CPDEPAPRCPAGVSLVLDGCGCCRVCAKQLGELCTERDPCDPHKGLFC), domain I+II (sequence Met1CPDEPAPRCPAGVSLVLDGCGCCRVCAKQLGELCTERDPCDPHKGLFCCIFGGT VYRSGESFQSSCKYQCTCLDGAVGCMPLCSMDVRLPSPDCPFPRRVKLPGKCCEE) were cloned and expressed in 293 cells, and purified by Chelating SFF(Ni) Column, tested for single band by SEC and PAGE, and tested for absence of contamination. Domain-IV (sequence GKKCIRTPKISKPIKFELSGCTSMKTYRAKFCGVCTDGRCCTPHRTTTLPVEFKCPDGE VMKKNMMFIKTCACHYNCPGDNDIFESLYYRKMY) was purchased from Peprotech. Mouse or human DKK1 was generated from the coding sequence with some modifications and a tag. Secreted protein was harvested from 293 cells, and purified by nickel column, and tested for activity in a supertopflash (STF) assay 4. DKK1 showed EC50 of 0.69nM for WNT3a-induced WNT signaling in STF cells.
    [Show full text]
  • SRPK1 Acetylation Modulates Alternative Splicing to Regulate Cisplatin Resistance in Breast Cancer Cells
    ARTICLE https://doi.org/10.1038/s42003-020-0983-4 OPEN SRPK1 acetylation modulates alternative splicing to regulate cisplatin resistance in breast cancer cells Cheng Wang1, Zhihong Zhou2, Charannya Sozheesvari Subhramanyam1, Qiong Cao1, Zealyn Shi Lin Heng 1, ✉ Wen Liu 3, Xiangdong Fu 4 & Qidong Hu 1 1234567890():,; Cisplatin and other platinum-based compounds are frequently used to treat breast cancer, but their utility is severely compromised by drug resistance. Many genes dictating drug responsiveness are subject to pre-mRNA alternative splicing which is regulated by key kinases such as the serine-arginine protein kinase 1 (SRPK1). However, its contribution to drug resistance remains controversial. In this study, we have identified that Tip60-mediated acetylation of SRPK1 is closely associated with chemotherapy sensitivity. In breast cancer cells, cisplatin induced SRPK1 acetylation but in the corresponding resistant cells, it reduced acetylation yet increased phosphorylation and kinase activity of SRPK1, favouring the splicing of some anti-apoptotic variants. Significantly, the cisplatin-resistant cells could be re- sensitized by enhancing SRPK1 acetylation or inhibiting its kinase activity. Hence, our study reveals a key role of SRPK1 in the development of cisplatin resistance in breast cancer cells and suggests a potential therapeutic avenue for overcoming chemotherapy resistance. 1 Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, 4 Medical Drive, Singapore, Singapore 117594. 2 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 2 Medical Drive, Singapore, Singapore 117593. 3 School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiang’an South Road, Xiamen, Fujian 361102, China.
    [Show full text]
  • Cloning and Expression of Porcine SRPK1 Gene
    African Journal of Biotechnology Vol. 11(3), pp. 543-551, 10 January 2012, Available online at http://www.academicjournals.org/AJB DOI: 10.5897/AJB10.845 ISSN 1684–5315 © 2012 Academic Journals Full Length Research Paper Cloning and expression of porcine SRPK1 gene Guang-xin, E.1, Di Liu2*, Dong-Jie Zhang2, Xiu-Qin Yang1 and Ji-Yuan Zhu3 1Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100193, China 2Heilongjiang Academy of Agricultural Science, Harbin 150086, China. 3The First Affiliated Hospital of Haerbin Medical University, Harbin 15000, China. Accepted 5 August, 2011 Protein SRPK1 acts as a crucial element in the pre-initiation complex of transcription, which play an important role in the regulation procession of gene expression. This study was carried out in order to explore the genetic characteristic of SRPK1 in pigs. SRPK1 gene came from Yorkshire, a pig that was cloned by real time polymerase chain reaction (RT-PCR), yet coding sequence and partial 5’UTR sequence was completed. The distribution determination of mRNA taken from the heart, muscle, liver, kidney, lung stomach, small and large intestine, spleen and brain of ten Yorkshire and Duroc pigs was finished by real-time PCR by one day and 30 days old pigs. Expression test of gene SRPK1 was implemented in a skeletal damage model during the period of skeletal muscles development. Sequence analysis of a DNA fragment with a length of 2499 bp in gene SRPK1 of a Yorkshire pig revealed a full coding region that coded 656 AAs, yet including partial 5’UTR sequence. A total of 14 transcription binding sites were detected by bioinformatics analysis.
    [Show full text]
  • Aberrant Splicing and Drug Resistance in AML Rosalia De Necochea-Campion1, Geoffrey P
    de Necochea-Campion et al. Journal of Hematology & Oncology (2016) 9:85 DOI 10.1186/s13045-016-0315-9 REVIEW Open Access Aberrant splicing and drug resistance in AML Rosalia de Necochea-Campion1, Geoffrey P. Shouse2, Qi Zhou1, Saied Mirshahidi1 and Chien-Shing Chen1,2* Abstract The advent of next-generation sequencing technologies has unveiled a new window into the heterogeneity of acute myeloid leukemia (AML). In particular, recurrent mutations in spliceosome machinery and genome-wide aberrant splicing events have been recognized as a prominent component of this disease. This review will focus on how these factors influence drug resistance through altered splicing of tumor suppressor and oncogenes and dysregulation of the apoptotic signaling network. A better understanding of these factors in disease progression is necessary to design appropriate therapeutic strategies recognizing specific alternatively spliced or mutated oncogenic targets. Keywords: Splice factor, Chemoresistance, Mutation, Target, Clonal evolution Abbreviations: AML, Acute myeloid leukemia; MDS, Myelodysplastic syndromes; SR, Serine rich; hnRNP, Heterogenous nuclear ribonucleoproteins; RNA, Ribonucleic acid; SF3B1, Splicing factor 3b, subunit 1; SRSF2, Serine/arginine-rich splicing factor 2; U2AF1, U2 small nuclear RNA auxiliary factor 1; BCL-2, B cell lymphoma 2; IAP, Inhibitor of apoptosis; BIM, Bcl-2-like protein 11; SRSF1, Serine/arginine-rich splicing factor 1; mTORC1, Mammalian target of rapamycin complex 1; AKT, V-Akt murine thymoma viral oncogene homolog; STAT,
    [Show full text]
  • Pattern Discovery and Cancer Gene Identification in Integrated Cancer
    Pattern discovery and cancer gene identification in integrated cancer genomic data Qianxing Moa,b, Sijian Wangc, Venkatraman E. Seshana, Adam B. Olshend, Nikolaus Schultze, Chris Sandere, R. Scott Powersf, Marc Ladanyig, and Ronglai Shena,1 aDepartment of Epidemiology and Biostatistics, eComputational Biology Program, and gDepartment of Pathology and Human Oncology and Pathogenesis Program, Memorial Sloan–Kettering Cancer Center, New York, NY 10065; bDepartment of Medicine and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030; cDepartment of Biostatistics and Medical Informatics, University of Wisconsin, Madison, WI 53792; dDepartment of Epidemiology and Biostatistics, University of California, San Francisco, CA 94107; and fCancer Genome Center, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11797 Edited by Peter J. Bickel, University of California, Berkeley, CA, and approved December 19, 2012 (received for review May 27, 2012) Large-scale integrated cancer genome characterization efforts in- integrates the information to extract biological principles from the cluding the cancer genome atlas and the cancer cell line encyclo- massive amount of data to provide useful insights for advancing pedia have created unprecedented opportunities to study cancer diagnostic, prognostic, and therapeutic strategies. biology in the context of knowing the entire catalog of genetic In a previous publication (8), we proposed an integrative alterations. A clinically important challenge is to discover cancer clustering framework
    [Show full text]
  • Downloaded from the PDB Database [27]
    www.aging-us.com AGING 2021, Vol. 13, No. 1 Research Paper Identification of a novel and potent small molecule inhibitor of SRPK1: mechanism of dual inhibition of SRPK1 for the inhibition of cancer progression Anshuman Chandra1, Hanumappa Ananda2, Nagendra Singh1, Imteyaz Qamar1 1School of Biotechnology, Gautam Buddha University, Greater Noida, U.P. 201312, India 2Department of Clinical Embryology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India Correspondence to: Imteyaz Qamar, Nagendra Singh; email: [email protected]; [email protected], https://orcid.org/0000-0003-0419-0684 Keywords: splicing inhibitor, structure-based drug design, flow cytometry, MTT assay, virtual screening Received: May 21, 2020 Accepted: August 19, 2020 Published: December 3, 2020 Copyright: © 2020 Chandra et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Protein kinases are the family of attractive enzyme targets for drug design with relevance to cancer biology. Serine arginine protein kinase 1 (SRPK1) is responsible for the phosphorylation of serine/arginine (SR)-rich proteins. Alternative Splicing Factor/Splicing Factor 2 (ASF/SF2) involved in mRNA editing. ASF/SF2 is over expressed in many cancers and plays crucial roles in the cell survival. Phosphorylation of ASF/SF2 is decisive for its functions in cancer. In search of potential anticancer therapeutic agents for attenuating phosphorylation of ASF/SF2, we have explored specific and potential inhibitors of SRPK1 from natural and drug like compounds databases using in-silico methods.
    [Show full text]
  • Leveraging Models of Cell Regulation and GWAS Data in Integrative Network-Based Association Studies
    PERSPECTIVE Leveraging models of cell regulation and GWAS data in integrative network-based association studies Andrea Califano1–3,11, Atul J Butte4,5, Stephen Friend6, Trey Ideker7–9 & Eric Schadt10,11 Over the last decade, the genome-wide study of both heritable and straightforward: within the space of all possible genetic and epigenetic somatic human variability has gone from a theoretical concept to a variants, those contributing to a specific trait or disease likely have broadly implemented, practical reality, covering the entire spectrum some coalescent properties, allowing their effect to be functionally of human disease. Although several findings have emerged from these canalized via the cell communication and cell regulatory machin- studies1, the results of genome-wide association studies (GWAS) have ery that allows distinct cells to interact and regulates their behavior. been mostly sobering. For instance, although several genes showing Notably, contrary to random networks, whose output is essentially medium-to-high penetrance within heritable traits were identified by unconstrained, regulatory networks produced by adaptation to spe- these approaches, the majority of heritable genetic risk factors for most cific fitness landscapes are optimized to produce only a finite number common diseases remain elusive2–7. Additionally, due to impractical of well-defined outcomes as a function of a very large number of exog- requirements for cohort size8 and lack of methodologies to maximize enous and endogenous signals. Thus, if a comprehensive and accurate power for such detections, few epistatic interactions and low-pen- map of all intra- and intercellular molecular interactions were avail- etrance variants have been identified9. At the opposite end of the able, then genetic and epigenetic events implicated in a specific trait or germline versus somatic event spectrum, considering that tumor cells disease should cluster in subnetworks of closely interacting genes.
    [Show full text]
  • A Meta-Analysis of the Effects of High-LET Ionizing Radiations in Human Gene Expression
    Supplementary Materials A Meta-Analysis of the Effects of High-LET Ionizing Radiations in Human Gene Expression Table S1. Statistically significant DEGs (Adj. p-value < 0.01) derived from meta-analysis for samples irradiated with high doses of HZE particles, collected 6-24 h post-IR not common with any other meta- analysis group. This meta-analysis group consists of 3 DEG lists obtained from DGEA, using a total of 11 control and 11 irradiated samples [Data Series: E-MTAB-5761 and E-MTAB-5754]. Ensembl ID Gene Symbol Gene Description Up-Regulated Genes ↑ (2425) ENSG00000000938 FGR FGR proto-oncogene, Src family tyrosine kinase ENSG00000001036 FUCA2 alpha-L-fucosidase 2 ENSG00000001084 GCLC glutamate-cysteine ligase catalytic subunit ENSG00000001631 KRIT1 KRIT1 ankyrin repeat containing ENSG00000002079 MYH16 myosin heavy chain 16 pseudogene ENSG00000002587 HS3ST1 heparan sulfate-glucosamine 3-sulfotransferase 1 ENSG00000003056 M6PR mannose-6-phosphate receptor, cation dependent ENSG00000004059 ARF5 ADP ribosylation factor 5 ENSG00000004777 ARHGAP33 Rho GTPase activating protein 33 ENSG00000004799 PDK4 pyruvate dehydrogenase kinase 4 ENSG00000004848 ARX aristaless related homeobox ENSG00000005022 SLC25A5 solute carrier family 25 member 5 ENSG00000005108 THSD7A thrombospondin type 1 domain containing 7A ENSG00000005194 CIAPIN1 cytokine induced apoptosis inhibitor 1 ENSG00000005381 MPO myeloperoxidase ENSG00000005486 RHBDD2 rhomboid domain containing 2 ENSG00000005884 ITGA3 integrin subunit alpha 3 ENSG00000006016 CRLF1 cytokine receptor like
    [Show full text]