Original Article Differential Expression of MST4, STK25 and PDCD10 Between Benign Prostatic Hyperplasia and Prostate Cancer
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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. -
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Patterns of DNA methylation on the human X chromosome and use in analyzing X-chromosome inactivation by Allison Marie Cotton B.Sc., The University of Guelph, 2005 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in The Faculty of Graduate Studies (Medical Genetics) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) January 2012 © Allison Marie Cotton, 2012 Abstract The process of X-chromosome inactivation achieves dosage compensation between mammalian males and females. In females one X chromosome is transcriptionally silenced through a variety of epigenetic modifications including DNA methylation. Most X-linked genes are subject to X-chromosome inactivation and only expressed from the active X chromosome. On the inactive X chromosome, the CpG island promoters of genes subject to X-chromosome inactivation are methylated in their promoter regions, while genes which escape from X- chromosome inactivation have unmethylated CpG island promoters on both the active and inactive X chromosomes. The first objective of this thesis was to determine if the DNA methylation of CpG island promoters could be used to accurately predict X chromosome inactivation status. The second objective was to use DNA methylation to predict X-chromosome inactivation status in a variety of tissues. A comparison of blood, muscle, kidney and neural tissues revealed tissue-specific X-chromosome inactivation, in which 12% of genes escaped from X-chromosome inactivation in some, but not all, tissues. X-linked DNA methylation analysis of placental tissues predicted four times higher escape from X-chromosome inactivation than in any other tissue. Despite the hypomethylation of repetitive elements on both the X chromosome and the autosomes, no changes were detected in the frequency or intensity of placental Cot-1 holes. -
Genome-Wide DNA Methylation Analysis of KRAS Mutant Cell Lines Ben Yi Tew1,5, Joel K
www.nature.com/scientificreports OPEN Genome-wide DNA methylation analysis of KRAS mutant cell lines Ben Yi Tew1,5, Joel K. Durand2,5, Kirsten L. Bryant2, Tikvah K. Hayes2, Sen Peng3, Nhan L. Tran4, Gerald C. Gooden1, David N. Buckley1, Channing J. Der2, Albert S. Baldwin2 ✉ & Bodour Salhia1 ✉ Oncogenic RAS mutations are associated with DNA methylation changes that alter gene expression to drive cancer. Recent studies suggest that DNA methylation changes may be stochastic in nature, while other groups propose distinct signaling pathways responsible for aberrant methylation. Better understanding of DNA methylation events associated with oncogenic KRAS expression could enhance therapeutic approaches. Here we analyzed the basal CpG methylation of 11 KRAS-mutant and dependent pancreatic cancer cell lines and observed strikingly similar methylation patterns. KRAS knockdown resulted in unique methylation changes with limited overlap between each cell line. In KRAS-mutant Pa16C pancreatic cancer cells, while KRAS knockdown resulted in over 8,000 diferentially methylated (DM) CpGs, treatment with the ERK1/2-selective inhibitor SCH772984 showed less than 40 DM CpGs, suggesting that ERK is not a broadly active driver of KRAS-associated DNA methylation. KRAS G12V overexpression in an isogenic lung model reveals >50,600 DM CpGs compared to non-transformed controls. In lung and pancreatic cells, gene ontology analyses of DM promoters show an enrichment for genes involved in diferentiation and development. Taken all together, KRAS-mediated DNA methylation are stochastic and independent of canonical downstream efector signaling. These epigenetically altered genes associated with KRAS expression could represent potential therapeutic targets in KRAS-driven cancer. Activating KRAS mutations can be found in nearly 25 percent of all cancers1. -
Individualized Systems Medicine Strategy to Tailor Treatments for Patients with Chemorefractory Acute Myeloid Leukemia
Published OnlineFirst September 20, 2013; DOI: 10.1158/2159-8290.CD-13-0350 RESEARCH ARTICLE Individualized Systems Medicine Strategy to Tailor Treatments for Patients with Chemorefractory Acute Myeloid Leukemia Tea Pemovska 1 , Mika Kontro 2 , Bhagwan Yadav 1 , Henrik Edgren 1 , Samuli Eldfors1 , Agnieszka Szwajda 1 , Henrikki Almusa 1 , Maxim M. Bespalov 1 , Pekka Ellonen 1 , Erkki Elonen 2 , Bjørn T. Gjertsen5 , 6 , Riikka Karjalainen 1 , Evgeny Kulesskiy 1 , Sonja Lagström 1 , Anna Lehto 1 , Maija Lepistö1 , Tuija Lundán 3 , Muntasir Mamun Majumder 1 , Jesus M. Lopez Marti 1 , Pirkko Mattila 1 , Astrid Murumägi 1 , Satu Mustjoki 2 , Aino Palva 1 , Alun Parsons 1 , Tero Pirttinen 4 , Maria E. Rämet 4 , Minna Suvela 1 , Laura Turunen 1 , Imre Västrik 1 , Maija Wolf 1 , Jonathan Knowles 1 , Tero Aittokallio 1 , Caroline A. Heckman 1 , Kimmo Porkka 2 , Olli Kallioniemi 1 , and Krister Wennerberg 1 ABSTRACT We present an individualized systems medicine (ISM) approach to optimize cancer drug therapies one patient at a time. ISM is based on (i) molecular profi ling and ex vivo drug sensitivity and resistance testing (DSRT) of patients’ cancer cells to 187 oncology drugs, (ii) clinical implementation of therapies predicted to be effective, and (iii) studying consecutive samples from the treated patients to understand the basis of resistance. Here, application of ISM to 28 samples from patients with acute myeloid leukemia (AML) uncovered fi ve major taxonomic drug-response sub- types based on DSRT profi les, some with distinct genomic features (e.g., MLL gene fusions in subgroup IV and FLT3 -ITD mutations in subgroup V). Therapy based on DSRT resulted in several clinical responses. -
Mirna‑26A‑5P and Mir‑26B‑5P Inhibit the Proliferation of Bladder Cancer Cells by Regulating PDCD10
ONCOLOGY REPORTS 40: 3523-3532, 2018 miRNA‑26a‑5p and miR‑26b‑5p inhibit the proliferation of bladder cancer cells by regulating PDCD10 KE WU1*, XING-YU MU1*, JUN-TAO JIANG1, MING-YUE TAN1, REN-JIE WANG1, WEN-JIE ZHOU2, XIANG WANG1, YIN-YAN HE3, MING-QING LI2 and ZHI-HONG LIU1 1Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080; 2Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011; 3Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China Received October 11, 2017; Accepted September 4, 2018 DOI: 10.3892/or.2018.6734 Abstract. MicroRNA (miR)-26a-5p and miR-26b-5p consis- and miR-26b-5p were pivotal regulators in BC progression tently play an antitumor role in many types of cancers, but the by targeting the proliferation-related protein, PDCD10. The underlying mechanism remains unclear in bladder cancer (BC). miR-26-5p/PDCD10 interaction may provide important In the present study, we found that, in BC tissues, the levels of insight into the pathway of BC progression and present novel miR-26a-5p and miR-26b-5p were lower than in paired normal opportunities for future diagnosis and treatment strategies, tissues. The upregulation of miR‑26‑5p significantly inhibited especially for patients with high levels of PDCD10. the proliferation of BC cell lines (T24 and 5637). Bioinformatics analysis indicated that Programmed Cell Death 10 (PDCD10) Introduction was the downstream target gene of miR-26a-5p/miR-26b-5p, and this was ascertained by western blotting and quantitative Bladder cancer (BC) is one of the most important urinary real-time reverse transcription PCR (RT-qPCR). -
Structure-Based Screen Identification of a Mammalian Ste20-Like Kinase 4 (MST4) Inhibitor with Therapeutic Potential for Pituitary Tumors
Published OnlineFirst December 31, 2015; DOI: 10.1158/1535-7163.MCT-15-0703 Small Molecule Therapeutics Molecular Cancer Therapeutics Structure-Based Screen Identification of a Mammalian Ste20-like Kinase 4 (MST4) Inhibitor with Therapeutic Potential for Pituitary Tumors Weipeng Xiong1,3, Christopher J. Matheson2, Mei Xu1,3, Donald S. Backos2, Taylor S. Mills1, Smita Salian-Mehta1, Katja Kiseljak-Vassiliades1,3, Philip Reigan2, and Margaret E. Wierman1,3 Abstract Pituitary tumors of the gonadotrope lineage are often large described as an Aurora kinase inhibitor, exhibited potent inhi- and invasive, resulting in hypopituitarism. No medical treat- bition of the MST4 kinase at nanomolar concentrations. The ments are currently available. Using a combined genetic and LbT2 gonadotrope pituitary cell hypoxic model was used to test genomic screen of individual human gonadotrope pituitary the ability of this inhibitor to antagonize MST4 actions. Under tumor samples, we recently identified the mammalian ster- short-term severe hypoxia (1% O2), MST4 protection from ile-20 like kinase 4 (MST4) as a protumorigenic effector, driving hypoxia-induced apoptosis was abrogated in the presence of increased pituitary cell proliferation and survival in response to hesperadin. Similarly, under chronic hypoxia (5%), hesperadin a hypoxic microenvironment. To identify novel inhibitors of blocked the proliferative and colony-forming actions of MST4 the MST4 kinase for potential future clinical use, computation- as well as the ability to activate specific downstream signaling al-based virtual library screening was used to dock the Sell- and hypoxia-inducible factor-1 effectors. Together, these data eckChem kinase inhibitor library into the ATP-binding site of identify hesperadin as the first potent, selective inhibitor of the the MST4 crystal structure. -
Cerebral Cavernous Malformations: from Genes to Proteins to Disease
See the corresponding editorial in this issue, pp 119–121. J Neurosurg 116:122–132, 2012 Cerebral cavernous malformations: from genes to proteins to disease Clinical article DANIEL D. CAVALCANTI, M.D., M. YASHAR S. KALANI, M.D., PH.D., NIKOLAY L. MARTIROSYAN, M.D., JUSTIN EALES, B.S., ROBERT F. SPETZLER, M.D., AND MARK C. PREUL, M.D. Division of Neurological Surgery, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, Arizona Over the past half century molecular biology has led to great advances in our understanding of angio- and vas- culogenesis and in the treatment of malformations resulting from these processes gone awry. Given their sporadic and familial distribution, their developmental and pathological link to capillary telangiectasias, and their observed chromosomal abnormalities, cerebral cavernous malformations (CCMs) are regarded as akin to cancerous growths. Although the exact pathological mechanisms involved in the formation of CCMs are still not well understood, the identification of 3 genetic loci has begun to shed light on key developmental pathways involved in CCM pathogen- esis. Cavernous malformations can occur sporadically or in an autosomal dominant fashion. Familial forms of CCMs have been attributed to mutations at 3 different loci implicated in regulating important processes such as proliferation and differentiation of angiogenic precursors and members of the apoptotic machinery. These processes are important for the generation, maintenance, and pruning of every vessel in the body. In this review the authors highlight the lat- est discoveries pertaining to the molecular genetics of CCMs, highlighting potential new therapeutic targets for the treatment of these lesions. -
A Semantic Approach for Knowledge Capture of Microrna-Target Gene Interactions
2015 IEEE International Conference on Bioinformatics and Biomedicine (BIBM) A semantic approach for knowledge capture of microRNA-target gene interactions Jingshan Huang* Fernando Gutierrez Dejing Dou School of Computing, University of South Alabama CIS Dept., University of Oregon CIS Dept., University of Oregon Mobile, Alabama 36688, U.S.A. Eugene, Oregon 97403, U.S.A. Eugene, Oregon 97403, U.S.A. Judith A. Blake Karen Eilbeck Darren A. Natale The Jackson Laboratory School of Medicine, University of Utah Georgetown University Medical Center Bar Harbor, Maine 04609, U.S.A. Salt Lake City, Utah 84112, U.S.A. Washington D.C. 20007, U.S.A. Barry Smith Yu Lin Xiaowei Wang Dept. Philosophy, University at Buffalo University of Miami Washington University School of Medicine Buffalo, New York 14260, U.S.A. Miami, Florida 33146, U.S.A. St. Louis, Missouri 63110, U.S.A. Zixing Liu Ming Tan Alan Ruttenberg MCI, University of South Alabama MCI, University of South Alabama Dental Medicine, University at Buffalo Mobile, Alabama 36604, U.S.A. Mobile, Alabama 36604, U.S.A. Buffalo, New York 14214, U.S.A. Abstract—Research has indicated that microRNAs (miRNAs), Conventionally, data end users (that is, biologists, bioin- a special class of non-coding RNAs (ncRNAs), can perform formaticians, and clinical investigators) need to search for important roles in different biological and pathological processes. (1) biologically validated miRNA targets (for example, by miRNAs’ functions are realized by regulating their respective querying the PubMed database [3]) and (2) computationally target genes (targets). It is thus critical to identify and analyze putative miRNA targets (for example, by initiating inquiries miRNA-target interactions for a better understanding and de- on various prediction databases or websites such as miRDB lineation of miRNAs’ functions. -
STRIPAK Complexes in Cell Signaling and Cancer
Oncogene (2016), 1–9 © 2016 Macmillan Publishers Limited All rights reserved 0950-9232/16 www.nature.com/onc REVIEW STRIPAK complexes in cell signaling and cancer Z Shi1,2, S Jiao1 and Z Zhou1,3 Striatin-interacting phosphatase and kinase (STRIPAK) complexes are striatin-centered multicomponent supramolecular structures containing both kinases and phosphatases. STRIPAK complexes are evolutionarily conserved and have critical roles in protein (de) phosphorylation. Recent studies indicate that STRIPAK complexes are emerging mediators and regulators of multiple vital signaling pathways including Hippo, MAPK (mitogen-activated protein kinase), nuclear receptor and cytoskeleton remodeling. Different types of STRIPAK complexes are extensively involved in a variety of fundamental biological processes ranging from cell growth, differentiation, proliferation and apoptosis to metabolism, immune regulation and tumorigenesis. Growing evidence correlates dysregulation of STRIPAK complexes with human diseases including cancer. In this review, we summarize the current understanding of the assembly and functions of STRIPAK complexes, with a special focus on cell signaling and cancer. Oncogene advance online publication, 15 February 2016; doi:10.1038/onc.2016.9 INTRODUCTION in the central nervous system and STRN4 is mostly abundant in Recent proteomic studies identified a group of novel multi- the brain and lung, whereas STRN3 is ubiquitously expressed in 5–9 component complexes named striatin (STRN)-interacting phos- almost all tissues. STRNs share a -
HHS Public Access Author Manuscript
HHS Public Access Author manuscript Author Manuscript Author ManuscriptGenet Med Author Manuscript. Author manuscript; Author Manuscript available in PMC 2016 March 01. Published in final edited form as: Genet Med. 2015 March ; 17(3): 188–196. doi:10.1038/gim.2014.97. EXCEPTIONAL AGGRESSIVENESS OF CEREBRAL CAVERNOUS MALFORMATION DISEASE ASSOCIATED WITH PDCD10 MUTATIONS Robert Shenkar, PhD#1, Changbin Shi, MD, PhD#1, Tania Rebeiz, MD2, Rebecca A. Stockton, PhD3, David A. McDonald, PhD4,5, Abdul Ghani Mikati, MD1, Lingjiao Zhang, MS1, Cecilia Austin, BS1, Amy L. Akers, PhD6, Carol J. Gallione, BA4, Autumn Rorrer, BA4, Murat Gunel, MD7, Wang Min, PhD8, Jorge Marcondes De Souza, MD, PhD9, Connie Lee, PsyD6, Douglas A. Marchuk, PhD#4, and Issam A. Awad, MD, MSc#1,2 1Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago Medicine, Chicago, IL 60637, USA 2Department of Neurology, The University of Chicago Medicine, Chicago, IL 60637, USA 3Department of Pediatrics, University of California at Los Angeles, Torrance, CA 90502, USA 4Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27710, USA 5Center for Science, Math and Technology Education, North Carolina Central University, Durham, NC 27707, USA 6Angioma Alliance, Norfolk, VA 23510, USA 7Departments of Neurosurgery and Neurobiology, Yale University, New Haven, CT 06520, USA 8Department of Pathology, Yale University, New Haven, CT 06520, USA 9Department of Neurosurgery, School of Medicine, Federal University of Rio De Janeiro, Rio de Janeiro, Brazil # These authors contributed equally to this work. Abstract Purpose—The phenotypic manifestations of cerebral cavernous malformation (CCM) disease caused by rare PDCD10 mutations have not been systematically examined, and a mechanistic link to Rho kinase (ROCK) mediated hyperpermeability, a potential therapeutic target, has not been established. -
Identification of Endogenous Adenomatous Polyposis Coli Interaction Partners and B-Catenin– Independent Targets by Proteomics
Published OnlineFirst June 3, 2019; DOI: 10.1158/1541-7786.MCR-18-1154 Cancer "-omics" Molecular Cancer Research Identification of Endogenous Adenomatous Polyposis Coli Interaction Partners and b-Catenin– Independent Targets by Proteomics Olesja Popow1,2,3,Joao~ A. Paulo2, Michael H. Tatham4, Melanie S. Volk3, Alejandro Rojas-Fernandez5, Nicolas Loyer3, Ian P. Newton3, Jens Januschke3, Kevin M. Haigis1,6, and Inke Nathke€ 3 Abstract Adenomatous Polyposis Coli (APC) is the most frequently tion between endogenous MINK1 and APC and further mutated gene in colorectal cancer. APC negatively regulates confirmed the negative, and b-catenin–independent, regu- the Wnt signaling pathway by promoting the degradation of lation of MINK1 by APC. Increased Mink1/Msn levels were b-catenin, but the extent to which APC exerts Wnt/b-cate- also observed in mouse intestinal tissue and Drosophila nin–independent tumor-suppressive activity is unclear. To follicular cells expressing mutant Apc/APC when compared identify interaction partners and b-catenin–independent with wild-type tissue/cells. Collectively, our results highlight targets of endogenous, full-length APC, we applied label- the extent and importance of Wnt-independent APC func- free and multiplexed tandem mass tag-based mass spec- tions in epithelial biology and disease. trometry. Affinity enrichment-mass spectrometry identified more than 150 previously unidentified APC interaction Implications: The tumor-suppressive function of APC, the partners. Moreover, our global proteomic analysis revealed most frequently mutated gene in colorectal cancer, is mainly that roughly half of the protein expression changes that attributed to its role in b-catenin/Wnt signaling. Our study occur in response to APC loss are independent of b-catenin. -
Cerebral Cavernous Malformation Proteins in Barrier Maintenance and Regulation
International Journal of Molecular Sciences Review Cerebral Cavernous Malformation Proteins in Barrier Maintenance and Regulation 1,2, 2, 3 2 3 Shu Wei y, Ye Li y, Sean P. Polster , Christopher R. Weber , Issam A. Awad and Le Shen 2,3,* 1 Graduate Program in Public Health and Preventive Medicine, Wuhan University of Science and Technology, Wuhan 430081, China; [email protected] 2 Department of Pathology, The University of Chicago, Chicago, IL 60615, USA; [email protected] (Y.L.); [email protected] (C.R.W.) 3 Section of Neurosurgery, Department of Surgery, The University of Chicago, Chicago, IL 60615, USA; [email protected] (S.P.P.); [email protected] (I.A.A.) * Correspondence: [email protected] These authors contributed equally. y Received: 10 December 2019; Accepted: 15 January 2020; Published: 20 January 2020 Abstract: Cerebral cavernous malformation (CCM) is a disease characterized by mulberry shaped clusters of dilated microvessels, primarily in the central nervous system. Such lesions can cause seizures, headaches, and stroke from brain bleeding. Loss-of-function germline and somatic mutations of a group of genes, called CCM genes, have been attributed to disease pathogenesis. In this review, we discuss the impact of CCM gene encoded proteins on cellular signaling, barrier function of endothelium and epithelium, and their contribution to CCM and potentially other diseases. Keywords: cerebral cavernous malformation; endothelial barrier; epithelial barrier; Rho; ROCK; MEKK3 1. Introduction One of the key functions of endothelial and epithelial cells is to create a barrier that separates different tissue compartments, and in the case of skin, epithelial cells separate body and outer environment.