Table S13. Comparison of P-Loop Gtpases in R. Oryzae and Dikaryotic Fungi
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Autophagy: from Basic Science to Clinical Application
nature publishing group REVIEW See COMMENTARY page XX Autophagy: from basic science to clinical application J Va n L i m b e r g e n 1 , 2 , 3 , C S t e v e n s 4 , E R N i m m o 1 , D C W i l s o n 2 , 3 a n d J S a t s a n g i 1 Autophagy is a cellular pathway involved in protein and organelle degradation, which is likely to represent an innate adaptation to starvation. In times of nutrient deficiency, the cell can self-digest and recycle some nonessential components through nonselective autophagy, thus sustaining minimal growth requirements until a food source becomes available. Over recent years, autophagy has been implicated in an increasing number of clinical scenarios, notably infectious diseases, cancer, neurodegenerative diseases, and autoimmunity. The recent identification of the importance of autophagy genes in the genetic susceptibility to Crohn ’ s disease suggests that a selective autophagic response may play a crucial role in the pathogenesis of common complex immune-mediated diseases. In this review, we discuss the autophagic mechanisms, their molecular regulation, and summarize their clinical relevance. This progress has led to great interest in the therapeutic potential of manipulation of both selective and nonselective autophagy in established disease. INTRODUCTION The ability to adapt to environmental change is essential for sur- Autophagy encompasses several distinct processes involving vival. This is true for the organism as a whole and for individual the delivery of portions of the cytoplasm to the lysosome for cells alike. -
Characterization of Gf a Drosophila Trimeric G Protein Alpha Subunit
Characterization of Gf a Drosophila trimeric G protein alpha subunit Naureen Quibria Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2012 © 2012 Naureen Quibria All rights reserved Abstract Characterization of Gf a Drosophila trimeric G-protein alpha subunit Naureen Quibria In the morphogenesis of tissue development, how coordination of patterning and growth achieve the correct organ size and shape is a principal question in biology. Efficient orchestrating mechanisms are required to achieve this and cells have developed sophisticated systems for reception and interpretation of the multitude of extracellular stimuli to which they are exposed. Plasma membrane receptors play a key role in the transmission of such signals. G-protein coupled receptors (GPCRs) are the largest class of cell surface receptors that respond to an enormous diversity of extracellular stimuli, and are critical mediators of cellular signal transduction in eukaryotic organisms. Signaling through GPCRs has been well characterized in many biological contexts. While they are a major class of signal transducers, there are not many defined instances where GPCRs have been implicated in the process of development to date. The Drosophila wing provides an ideal model system to elucidate and address the role of GPCRs in development, as its growth is regulated by a small number of conserved signaling pathways. In my thesis work, I address the role of a trimeric G alpha protein in Drosophila, Gαf, and what part it may play in development. In particular, I explore the role of Gαf as an alpha subunit of a trimeric complex, to determine what heptahelical receptors might act as its cognate receptor. -
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. -
Supplemental Table S1
Electronic Supplementary Material (ESI) for Molecular Omics. This journal is © The Royal Society of Chemistry 2020 Supplemental table S1: List of proteins identified following MS analysis of the proteins removed of N-linked glycans and isolated from gels with an increased abundance in TIS Cal51 cells induced with paclitaxel versus control Cal51 cells. Protein in increased abundance in TIS vs control WCL Accession Fold Change Anova (P) Plectin Q15149 1.073855593 0.00691631 Ras GTPase-activating-like protein IQGAP1 P46940 1.087337643 0.0176342 Elongation factor1-gamma P26641 1.138709703 0.0116496 Peptidyl-prolyl cis-transisomerase B P23284 1.188383105 0.0436246 Dipeptidyl peptidase 3 Q9NY33 1.20163605 0.0215448 Transitional endoplasmic reticulum ATPase P55072 1.214194884 0.0449691 Carbonic anhydrase 2 P00918 1.232852325 0.0158141 Clathrin heavy chain 1 Q00610 1.239621773 0.0463237 Protein transport protein Sec 31A O94979 1.263565104 0.0284155 Aldo-ketoreductase family 1 member C1 Q04828 1.282092186 0.0324406 Spermidine synthase P19623 1.298728621 0.0196232 Plastin-3 P13797 1.310756772 0.0161319 Actin-related protein 2/3 complex subunit 5 O15511 1.333483524 0.00476923 Actin-related protein 2/3 complex subunit 2 O15144 1.35416168 0.0411018 Proteasome subunit alpha type-5 P28066 1.358015551 0.0337657 Thioredoxin reductase 1, cytoplasmic Q16881 1.383670089 0.0235472 Acyl-protein thioesterase 2 O95372 1.387415589 0.00233899 Isoaspartylpeptidase/L-asparaginase Q7L266 1.408149002 0.0319602 Splicing factor U2AF 65kDa subunit P26368 1.41489991 0.0256619 -
Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/Mtor Cascade Inhibitors: How Mutations Can Result in Therapy Resistance and How to Overcome Resistance
www.impactjournals.com/oncotarget/ Oncotarget, October, Vol.3, No 10 Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Cascade Inhibitors: How Mutations Can Result in Therapy Resistance and How to Overcome Resistance James A. McCubrey1, Linda S. Steelman1, William H. Chappell1, Stephen L. Abrams1, Richard A. Franklin1, Giuseppe Montalto2, Melchiorre Cervello3, Massimo Libra4, Saverio Candido4, Grazia Malaponte4, Maria C. Mazzarino4, Paolo Fagone4, Ferdinando Nicoletti4, Jörg Bäsecke5, Sanja Mijatovic6, Danijela Maksimovic- Ivanic6, Michele Milella7, Agostino Tafuri8, Francesca Chiarini9, Camilla Evangelisti9, Lucio Cocco10, Alberto M. Martelli9,10 1 Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA 2 Department of Internal Medicine and Specialties, University of Palermo, Palermo, Italy 3 Consiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare “Alberto Monroy”, Palermo, Italy 4 Department of Bio-Medical Sciences, University of Catania, Catania, Italy 5 Department of Medicine, University of Göttingen, Göttingen, Germany 6 Department of Immunology, Instititue for Biological Research “Sinisa Stankovic”, University of Belgrade, Belgrade, Serbia 7 Regina Elena National Cancer Institute, Rome, Italy 8 Sapienza, University of Rome, Department of Cellular Biotechnology and Hematology, Rome, Italy 9 Institute of Molecular Genetics, National Research Council-Rizzoli Orthopedic Institute, Bologna, Italy. 10 Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy Correspondence to: James A. McCubrey, email: [email protected] Keywords: Targeted Therapy, Therapy Resistance, Cancer Stem Cells, Raf, Akt, PI3K, mTOR Received: September 12, 2012, Accepted: October 18, 2012, Published: October 20, 2012 Copyright: © McCubrey et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. -
Melanomas Are Comprised of Multiple Biologically Distinct Categories
Melanomas are comprised of multiple biologically distinct categories, which differ in cell of origin, age of onset, clinical and histologic presentation, pattern of metastasis, ethnic distribution, causative role of UV radiation, predisposing germ line alterations, mutational processes, and patterns of somatic mutations. Neoplasms are initiated by gain of function mutations in one of several primary oncogenes, typically leading to benign melanocytic nevi with characteristic histologic features. The progression of nevi is restrained by multiple tumor suppressive mechanisms. Secondary genetic alterations override these barriers and promote intermediate or overtly malignant tumors along distinct progression trajectories. The current knowledge about pathogenesis, clinical, histological and genetic features of primary melanocytic neoplasms is reviewed and integrated into a taxonomic framework. THE MOLECULAR PATHOLOGY OF MELANOMA: AN INTEGRATED TAXONOMY OF MELANOCYTIC NEOPLASIA Boris C. Bastian Corresponding Author: Boris C. Bastian, M.D. Ph.D. Gerson & Barbara Bass Bakar Distinguished Professor of Cancer Biology Departments of Dermatology and Pathology University of California, San Francisco UCSF Cardiovascular Research Institute 555 Mission Bay Blvd South Box 3118, Room 252K San Francisco, CA 94158-9001 [email protected] Key words: Genetics Pathogenesis Classification Mutation Nevi Table of Contents Molecular pathogenesis of melanocytic neoplasia .................................................... 1 Classification of melanocytic neoplasms -
The Small Gtpase Rheb Affects Central Brain Neuronal Morphology and Memory Formation in Drosophila
The Small GTPase Rheb Affects Central Brain Neuronal Morphology and Memory Formation in Drosophila Heather L. D. Brown1¤a, Karla R. Kaun2¤b, Bruce A. Edgar1*¤c 1 Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America, 2 Department of Anatomy, University of California San Francisco, San Francisco, California, United States of America Abstract Mutations in either of two tumor suppressor genes, TSC1 or TSC2, cause tuberous sclerosis complex (TSC), a syndrome resulting in benign hamartomatous tumors and neurological disorders. Cellular growth defects and neuronal disorganization associated with TSC are believed to be due to upregulated TOR signaling. We overexpressed Rheb, an upstream regulator of TOR, in two different subsets of D. melanogaster central brain neurons in order to upregulate the Tsc- Rheb-TOR pathway. Overexpression of Rheb in either the mushroom bodies or the insulin producing cells resulted in enlarged axon projections and cell bodies, which continued to increase in size with prolonged Rheb expression as the animals aged. Additionally, Rheb overexpression in the mushroom bodies resulted in deficiencies in 3 hr but not immediate appetitive memory. Thus, Rheb overexpression in the central brain neurons of flies causes not only morphological phenotypes, but behavioral and aging phenotypes that may mirror symptoms of TSC. Citation: Brown HLD, Kaun KR, Edgar BA (2012) The Small GTPase Rheb Affects Central Brain Neuronal Morphology and Memory Formation in Drosophila. PLoS ONE 7(9): e44888. doi:10.1371/journal.pone.0044888 Editor: Shree Ram Singh, National Cancer Institute, United States of America Received February 28, 2012; Accepted August 14, 2012; Published September 19, 2012 Copyright: ß 2012 Brown et al. -
Human Induced Pluripotent Stem Cell–Derived Podocytes Mature Into Vascularized Glomeruli Upon Experimental Transplantation
BASIC RESEARCH www.jasn.org Human Induced Pluripotent Stem Cell–Derived Podocytes Mature into Vascularized Glomeruli upon Experimental Transplantation † Sazia Sharmin,* Atsuhiro Taguchi,* Yusuke Kaku,* Yasuhiro Yoshimura,* Tomoko Ohmori,* ‡ † ‡ Tetsushi Sakuma, Masashi Mukoyama, Takashi Yamamoto, Hidetake Kurihara,§ and | Ryuichi Nishinakamura* *Department of Kidney Development, Institute of Molecular Embryology and Genetics, and †Department of Nephrology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; ‡Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima, Japan; §Division of Anatomy, Juntendo University School of Medicine, Tokyo, Japan; and |Japan Science and Technology Agency, CREST, Kumamoto, Japan ABSTRACT Glomerular podocytes express proteins, such as nephrin, that constitute the slit diaphragm, thereby contributing to the filtration process in the kidney. Glomerular development has been analyzed mainly in mice, whereas analysis of human kidney development has been minimal because of limited access to embryonic kidneys. We previously reported the induction of three-dimensional primordial glomeruli from human induced pluripotent stem (iPS) cells. Here, using transcription activator–like effector nuclease-mediated homologous recombination, we generated human iPS cell lines that express green fluorescent protein (GFP) in the NPHS1 locus, which encodes nephrin, and we show that GFP expression facilitated accurate visualization of nephrin-positive podocyte formation in -
UTR Shortening Is a Molecular Signature of Mtorc1 Activation
ARTICLE Received 22 Sep 2014 | Accepted 18 Apr 2015 | Published 15 Jun 2015 DOI: 10.1038/ncomms8218 mRNA 30-UTR shortening is a molecular signature of mTORC1 activation Jae-Woong Chang1,*, Wei Zhang2,*, Hsin-Sung Yeh1, Ebbing P. de Jong1, Semo Jun1, Kwan-Hyun Kim1, Sun S. Bae3, Kenneth Beckman4, Tae Hyun Hwang5, Kye-Seong Kim6, Do-Hyung Kim1, Timothy J. Griffin1, Rui Kuang2 & Jeongsik Yong1 Mammalian target of rapamycin (mTOR) enhances translation from a subset of messenger RNAs containing distinct 50-untranslated region (UTR) sequence features. Here we identify 30-UTR shortening of mRNAs as an additional molecular signature of mTOR activation and show that 30-UTR shortening enhances the translation of specific mRNAs. Using genetic or chemical modulations of mTOR activity in cells or mouse tissues, we show that cellular mTOR activity is crucial for 30-UTR shortening. Although long 30-UTR-containing transcripts minimally contribute to translation, 3-0UTR-shortened transcripts efficiently form polysomes in the mTOR-activated cells, leading to increased protein production. Strikingly, selected E2 and E3 components of ubiquitin ligase complexes are enriched by this mechanism, resulting in elevated levels of protein ubiquitination on mTOR activation. Together, these findings identify a previously uncharacterized role for mTOR in the selective regulation of protein synthesis by modulating 30-UTR length of mRNAs. 1 Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota Twin Cities, 321 Church Street, SE 6-155 Jackson Hall, Minneapolis, Minnesota 55455, USA. 2 Department of Computer Science and Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA. 3 Department of Pharmacology, Pusan National University School of Medicine, Yangsan 626-870, Republic of Korea. -
Drosophila and Human Transcriptomic Data Mining Provides Evidence for Therapeutic
Drosophila and human transcriptomic data mining provides evidence for therapeutic mechanism of pentylenetetrazole in Down syndrome Author Abhay Sharma Institute of Genomics and Integrative Biology Council of Scientific and Industrial Research Delhi University Campus, Mall Road Delhi 110007, India Tel: +91-11-27666156, Fax: +91-11-27662407 Email: [email protected] Nature Precedings : hdl:10101/npre.2010.4330.1 Posted 5 Apr 2010 Running head: Pentylenetetrazole mechanism in Down syndrome 1 Abstract Pentylenetetrazole (PTZ) has recently been found to ameliorate cognitive impairment in rodent models of Down syndrome (DS). The mechanism underlying PTZ’s therapeutic effect is however not clear. Microarray profiling has previously reported differential expression of genes in DS. No mammalian transcriptomic data on PTZ treatment however exists. Nevertheless, a Drosophila model inspired by rodent models of PTZ induced kindling plasticity has recently been described. Microarray profiling has shown PTZ’s downregulatory effect on gene expression in fly heads. In a comparative transcriptomics approach, I have analyzed the available microarray data in order to identify potential mechanism of PTZ action in DS. I find that transcriptomic correlates of chronic PTZ in Drosophila and DS counteract each other. A significant enrichment is observed between PTZ downregulated and DS upregulated genes, and a significant depletion between PTZ downregulated and DS dowwnregulated genes. Further, the common genes in PTZ Nature Precedings : hdl:10101/npre.2010.4330.1 Posted 5 Apr 2010 downregulated and DS upregulated sets show enrichment for MAP kinase pathway. My analysis suggests that downregulation of MAP kinase pathway may mediate therapeutic effect of PTZ in DS. Existing evidence implicating MAP kinase pathway in DS supports this observation. -
Supplementary Table 1. Mutated Genes That Contain Protein Domains Identified Through Mutation Enrichment Analysis
Supplementary Table 1. Mutated genes that contain protein domains identified through mutation enrichment analysis A. Breast cancers InterPro ID Mutated genes (number of mutations) IPR000219 ARHGEF4(2), ECT2(1), FARP1(1), FLJ20184(1), MCF2L2(1), NET1(1), OBSCN(5), RASGRF2(2), TRAD(1), VAV3(1) IPR000225 APC2(2), JUP(1), KPNA5(2), SPAG6(1) IPR000357 ARFGEF2(2), CMYA4(1), DRIM(2), JUP(1), KPNA5(2), PIK3R4(1), SPAG6(1) IPR000533 AKAP9(2), C10orf39(1), C20orf23(1), CUTL1(1), HOOK1(1), HOOK3(1), KTN1(2), LRRFIP1(3), MYH1(3), MYH9(2), NEF3(1), NF2(1), RSN(1), TAX1BP1(1), TPM4(1) IPR000694 ADAM12(3), ADAMTS19(1), APC2(2), APXL(1), ARID1B(1), BAT2(2), BAT3(1), BCAR1(1), BCL11A(2), BCORL1(1), C14orf155(3), C1orf2(1), C1QB(1), C6orf31(1), C7orf11(1), CD2(1), CENTD3(3), CHD5(3), CIC(3), CMYA1(2), COL11A1(3), COL19A1(2), COL7A1(3), DAZAP1(1), DBN1(3), DVL3(1), EIF5(1), FAM44A(1), FAM47B(1), FHOD1(1), FLJ20584(1), G3BP2(2), GAB1(2), GGA3(1), GLI1(3), GPNMB(2), GRIN2D(3), HCN3(1), HOXA3(2), HOXA4(1), IRS4(1), KCNA5(1), KCNC2(1), LIP8(1), LOC374955(1), MAGEE1(2), MICAL1(2), MICAL‐L1(1), MLLT2(1), MMP15(1), N4BP2(1), NCOA6(2), NHS(1), NUP214(3), ODZ1(3), PER1(2), PER2(1), PHC1(1), PLXNB1(1), PPM1E(2), RAI17(2), RAPH1(2), RBAF600(2), SCARF2(1), SEMA4G(1), SLC16A2(1), SORBS1(1), SPEN(2), SPG4(1), TBX1(1), TCF1(2), TCF7L1(1), TESK1(1), THG‐1(1), TP53(18), TRIF(1), ZBTB3(2), ZNF318(2) IPR000909 CENTB1(2), PLCB1(1), PLCG1(1) IPR000998 AEGP(3), EGFL6(2), PRSS7(1) IPR001140 ABCB10(2), ABCB6(1), ABCB8(2) IPR001164 ARFGAP3(1), CENTB1(2), CENTD3(3), CENTG1(2) IPR001589 -
Small Gtpases of the Ras and Rho Families Switch On/Off Signaling
International Journal of Molecular Sciences Review Small GTPases of the Ras and Rho Families Switch on/off Signaling Pathways in Neurodegenerative Diseases Alazne Arrazola Sastre 1,2, Miriam Luque Montoro 1, Patricia Gálvez-Martín 3,4 , Hadriano M Lacerda 5, Alejandro Lucia 6,7, Francisco Llavero 1,6,* and José Luis Zugaza 1,2,8,* 1 Achucarro Basque Center for Neuroscience, Science Park of the Universidad del País Vasco/Euskal Herriko Unibertsitatea (UPV/EHU), 48940 Leioa, Spain; [email protected] (A.A.S.); [email protected] (M.L.M.) 2 Department of Genetics, Physical Anthropology, and Animal Physiology, Faculty of Science and Technology, UPV/EHU, 48940 Leioa, Spain 3 Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Granada, 180041 Granada, Spain; [email protected] 4 R&D Human Health, Bioibérica S.A.U., 08950 Barcelona, Spain 5 Three R Labs, Science Park of the UPV/EHU, 48940 Leioa, Spain; [email protected] 6 Faculty of Sport Science, European University of Madrid, 28670 Madrid, Spain; [email protected] 7 Research Institute of the Hospital 12 de Octubre (i+12), 28041 Madrid, Spain 8 IKERBASQUE, Basque Foundation for Science, 48013 Bilbao, Spain * Correspondence: [email protected] (F.L.); [email protected] (J.L.Z.) Received: 25 July 2020; Accepted: 29 August 2020; Published: 31 August 2020 Abstract: Small guanosine triphosphatases (GTPases) of the Ras superfamily are key regulators of many key cellular events such as proliferation, differentiation, cell cycle regulation, migration, or apoptosis. To control these biological responses, GTPases activity is regulated by guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs), and in some small GTPases also guanine nucleotide dissociation inhibitors (GDIs).