P. Azad Et Al. 3 SI Table S2 Total Genes Screened in Psup P- G
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Aberrant Modulation of Ribosomal Protein S6 Phosphorylation Confers Acquired Resistance to MAPK Pathway Inhibitors in BRAF-Mutant Melanoma
www.nature.com/aps ARTICLE Aberrant modulation of ribosomal protein S6 phosphorylation confers acquired resistance to MAPK pathway inhibitors in BRAF-mutant melanoma Ming-zhao Gao1,2, Hong-bin Wang1,2, Xiang-ling Chen1,2, Wen-ting Cao1,LiFu1, Yun Li1, Hai-tian Quan1,2, Cheng-ying Xie1,2 and Li-guang Lou1,2 BRAF and MEK inhibitors have shown remarkable clinical efficacy in BRAF-mutant melanoma; however, most patients develop resistance, which limits the clinical benefit of these agents. In this study, we found that the human melanoma cell clones, A375-DR and A375-TR, with acquired resistance to BRAF inhibitor dabrafenib and MEK inhibitor trametinib, were cross resistant to other MAPK pathway inhibitors. In these resistant cells, phosphorylation of ribosomal protein S6 (rpS6) but not phosphorylation of ERK or p90 ribosomal S6 kinase (RSK) were unable to be inhibited by MAPK pathway inhibitors. Notably, knockdown of rpS6 in these cells effectively downregulated G1 phase-related proteins, including RB, cyclin D1, and CDK6, induced cell cycle arrest, and inhibited proliferation, suggesting that aberrant modulation of rpS6 phosphorylation contributed to the acquired resistance. Interestingly, RSK inhibitor had little effect on rpS6 phosphorylation and cell proliferation in resistant cells, whereas P70S6K inhibitor showed stronger inhibitory effects on rpS6 phosphorylation and cell proliferation in resistant cells than in parental cells. Thus regulation of rpS6 phosphorylation, which is predominantly mediated by BRAF/MEK/ERK/RSK signaling in parental cells, was switched to mTOR/ P70S6K signaling in resistant cells. Furthermore, mTOR inhibitors alone overcame acquired resistance and rescued the sensitivity of the resistant cells when combined with BRAF/MEK inhibitors. -
Allele-Specific Expression of Ribosomal Protein Genes in Interspecific Hybrid Catfish
Allele-specific Expression of Ribosomal Protein Genes in Interspecific Hybrid Catfish by Ailu Chen A dissertation submitted to the Graduate Faculty of Auburn University in partial fulfillment of the requirements for the Degree of Doctor of Philosophy Auburn, Alabama August 1, 2015 Keywords: catfish, interspecific hybrids, allele-specific expression, ribosomal protein Copyright 2015 by Ailu Chen Approved by Zhanjiang Liu, Chair, Professor, School of Fisheries, Aquaculture and Aquatic Sciences Nannan Liu, Professor, Entomology and Plant Pathology Eric Peatman, Associate Professor, School of Fisheries, Aquaculture and Aquatic Sciences Aaron M. Rashotte, Associate Professor, Biological Sciences Abstract Interspecific hybridization results in a vast reservoir of allelic variations, which may potentially contribute to phenotypical enhancement in the hybrids. Whether the allelic variations are related to the downstream phenotypic differences of interspecific hybrid is still an open question. The recently developed genome-wide allele-specific approaches that harness high- throughput sequencing technology allow direct quantification of allelic variations and gene expression patterns. In this work, I investigated allele-specific expression (ASE) pattern using RNA-Seq datasets generated from interspecific catfish hybrids. The objective of the study is to determine the ASE genes and pathways in which they are involved. Specifically, my study investigated ASE-SNPs, ASE-genes, parent-of-origins of ASE allele and how ASE would possibly contribute to heterosis. My data showed that ASE was operating in the interspecific catfish system. Of the 66,251 and 177,841 SNPs identified from the datasets of the liver and gill, 5,420 (8.2%) and 13,390 (7.5%) SNPs were identified as significant ASE-SNPs, respectively. -
Eif2b Is a Decameric Guanine Nucleotide Exchange Factor with a G2e2 Tetrameric Core
ARTICLE Received 19 Feb 2014 | Accepted 15 Apr 2014 | Published 23 May 2014 DOI: 10.1038/ncomms4902 OPEN eIF2B is a decameric guanine nucleotide exchange factor with a g2e2 tetrameric core Yuliya Gordiyenko1,2,*, Carla Schmidt1,*, Martin D. Jennings3, Dijana Matak-Vinkovic4, Graham D. Pavitt3 & Carol V. Robinson1 eIF2B facilitates and controls protein synthesis in eukaryotes by mediating guanine nucleotide exchange on its partner eIF2. We combined mass spectrometry (MS) with chemical cross- linking, surface accessibility measurements and homology modelling to define subunit stoichiometry and interactions within eIF2B and eIF2. Although it is generally accepted that eIF2B is a pentamer of five non-identical subunits (a–e), here we show that eIF2B is a decamer. MS and cross-linking of eIF2B complexes allows us to propose a model for the subunit arrangements within eIF2B where the subunit assembly occurs through catalytic g- and e-subunits, with regulatory subunits arranged in asymmetric trimers associated with the core. Cross-links between eIF2 and eIF2B allow modelling of interactions that contribute to nucleotide exchange and its control by eIF2 phosphorylation. Finally, we identify that GTP binds to eIF2Bg, prompting us to propose a multi-step mechanism for nucleotide exchange. 1 Department of Chemistry, Physical and Theoretical Chemistry Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QZ, UK. 2 MRC Laboratory of Molecular Biology, University of Cambridge, Francis Crick Avenue, Cambridge CB2 0QH, UK. 3 Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK. 4 Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. -
Cofactor Dependent Conformational Switching of Gtpases
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector 1704 Biophysical Journal Volume 95 August 2008 1704–1715 Cofactor Dependent Conformational Switching of GTPases Vasili Hauryliuk,*y Sebastian Hansson,z and Ma˚ns Ehrenberg* *Department of Cell and Molecular Biology, Molecular Biology Program, Uppsala University, Uppsala, Sweden; yEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia; and zLaboratoire d’Enzymologie et Biochimie Structurales, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France ABSTRACT This theoretical work covers structural and biochemical aspects of nucleotide binding and GDP/GTP exchange of GTP hydrolases belonging to the family of small GTPases. Current models of GDP/GTP exchange regulation are often based on two specific assumptions. The first is that the conformation of a GTPase is switched by the exchange of the bound nucleotide from GDP to GTP or vice versa. The second is that GDP/GTP exchange is regulated by a guanine nucleotide exchange factor, which stabilizes a GTPase conformation with low nucleotide affinity. Since, however, recent biochemical and structural data seem to contradict this view, we present a generalized scheme for GTPase action. This novel ansatz accounts for those important cases when conformational switching in addition to guanine nucleotide exchange requires the presence of cofactors, and gives a more nuanced picture of how the nucleotide exchange is regulated. The scheme is also used to discuss some problems of interpretation that may arise when guanine nucleotide exchange mechanisms are inferred from experiments with analogs of GTP, like GDPNP, GDPCP, and GDP g S. -
A Dissertation Entitled Characterization of the CXCR4
A Dissertation entitled Characterization of the CXCR4-LASP1-eIF4F Axis in Triple-Negative Breast Cancer by Cory M Howard Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Doctor of Philosophy Degree in Biomedical Sciences ___________________________________________ Dayanidhi Raman, B.V.Sc., Ph.D., Committee Chair ___________________________________________ Amit Tiwari, Ph.D., Committee Member ___________________________________________ Ritu Chakravarti, Ph.D., Committee Member ___________________________________________ Nagalakshmi Nadiminty, Ph.D., Committee Member ___________________________________________ Saori Furuta, Ph.D., Committee Member ___________________________________________ Shi-He Liu, M.D., Committee Member ___________________________________________ Amanda C. Bryant-Friedrich, Ph.D., Dean College of Graduate Studies The University of Toledo August 2020 © 2020 Cory M. Howard This document is copyrighted material. Under copyright law, no parts of this document may be reproduced without the expressed permission of the author. An Abstract of Characterization of the CXCR4-LASP1-eIF4F Axis in Triple-Negative Breast Cancer by Cory M. Howard Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Doctor of Philosophy Degree in Biomedical Sciences The University of Toledo August 2020 Triple-negative breast cancer (TNBC) remains clinically challenging as effective targeted therapies are still lacking. In addition, patient mortality mainly results from the metastasized -
Mtorc1 Controls Mitochondrial Activity and Biogenesis Through 4E-BP-Dependent Translational Regulation
Cell Metabolism Article mTORC1 Controls Mitochondrial Activity and Biogenesis through 4E-BP-Dependent Translational Regulation Masahiro Morita,1,2 Simon-Pierre Gravel,1,2 Vale´ rie Che´ nard,1,2 Kristina Sikstro¨ m,3 Liang Zheng,4 Tommy Alain,1,2 Valentina Gandin,5,7 Daina Avizonis,2 Meztli Arguello,1,2 Chadi Zakaria,1,2 Shannon McLaughlan,5,7 Yann Nouet,1,2 Arnim Pause,1,2 Michael Pollak,5,6,7 Eyal Gottlieb,4 Ola Larsson,3 Julie St-Pierre,1,2,* Ivan Topisirovic,5,7,* and Nahum Sonenberg1,2,* 1Department of Biochemistry 2Goodman Cancer Research Centre McGill University, Montreal, QC H3A 1A3, Canada 3Department of Oncology-Pathology, Karolinska Institutet, Stockholm, 171 76, Sweden 4Cancer Research UK, The Beatson Institute for Cancer Research, Switchback Road, Glasgow G61 1BD, Scotland, UK 5Lady Davis Institute for Medical Research 6Cancer Prevention Center, Sir Mortimer B. Davis-Jewish General Hospital McGill University, Montreal, QC H3T 1E2, Canada 7Department of Oncology, McGill University, Montreal, QC H2W 1S6, Canada *Correspondence: [email protected] (J.S.-P.), [email protected] (I.T.), [email protected] (N.S.) http://dx.doi.org/10.1016/j.cmet.2013.10.001 SUMMARY ATP under physiological conditions in mammals and play a crit- ical role in overall energy balance (Vander Heiden et al., 2009). mRNA translation is thought to be the most energy- The mechanistic/mammalian target of rapamycin (mTOR) is a consuming process in the cell. Translation and serine/threonine kinase that has been implicated in a variety of energy metabolism are dysregulated in a variety of physiological processes and pathological states (Zoncu et al., diseases including cancer, diabetes, and heart 2011). -
Differential Requirement of the Ribosomal Protein S6 And
Plant Pathology and Microbiology Publications Plant Pathology and Microbiology 5-2017 Differential Requirement of the Ribosomal Protein S6 and Ribosomal Protein S6 Kinase for Plant- Virus Accumulation and Interaction of S6 Kinase with Potyviral VPg Minna-Liisa Rajamäki University of Helsinki Dehui Xi Sichuan University Sidona Sikorskaite-Gudziuniene University of Helsinki Jari P. T. Valkonen University of Helsinki Follow this and additional works at: http://lib.dr.iastate.edu/plantpath_pubs StevePanr tA of. W thehithAgramicultural Science Commons, Agriculture Commons, Plant Breeding and Genetics CIowommona State Usn, iaverndsit they, swPhithlanatm@i Pathoastalote.geduy Commons The ompc lete bibliographic information for this item can be found at http://lib.dr.iastate.edu/ plantpath_pubs/211. For information on how to cite this item, please visit http://lib.dr.iastate.edu/ howtocite.html. This Article is brought to you for free and open access by the Plant Pathology and Microbiology at Iowa State University Digital Repository. It has been accepted for inclusion in Plant Pathology and Microbiology Publications by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. Differential Requirement of the Ribosomal Protein S6 and Ribosomal Protein S6 Kinase for Plant-Virus Accumulation and Interaction of S6 Kinase with Potyviral VPg Abstract Ribosomal protein S6 (RPS6) is an indispensable plant protein regulated, in part, by ribosomal protein S6 kinase (S6K) which, in turn, is a key regulator of plant responses to stresses and developmental cues. Increased expression of RPS6 was detected in Nicotiana benthamiana during infection by diverse plant viruses. Silencing of the RPS6and S6K genes in N. -
Supplementary Table 2
Supplementary Table 2. Differentially Expressed Genes following Sham treatment relative to Untreated Controls Fold Change Accession Name Symbol 3 h 12 h NM_013121 CD28 antigen Cd28 12.82 BG665360 FMS-like tyrosine kinase 1 Flt1 9.63 NM_012701 Adrenergic receptor, beta 1 Adrb1 8.24 0.46 U20796 Nuclear receptor subfamily 1, group D, member 2 Nr1d2 7.22 NM_017116 Calpain 2 Capn2 6.41 BE097282 Guanine nucleotide binding protein, alpha 12 Gna12 6.21 NM_053328 Basic helix-loop-helix domain containing, class B2 Bhlhb2 5.79 NM_053831 Guanylate cyclase 2f Gucy2f 5.71 AW251703 Tumor necrosis factor receptor superfamily, member 12a Tnfrsf12a 5.57 NM_021691 Twist homolog 2 (Drosophila) Twist2 5.42 NM_133550 Fc receptor, IgE, low affinity II, alpha polypeptide Fcer2a 4.93 NM_031120 Signal sequence receptor, gamma Ssr3 4.84 NM_053544 Secreted frizzled-related protein 4 Sfrp4 4.73 NM_053910 Pleckstrin homology, Sec7 and coiled/coil domains 1 Pscd1 4.69 BE113233 Suppressor of cytokine signaling 2 Socs2 4.68 NM_053949 Potassium voltage-gated channel, subfamily H (eag- Kcnh2 4.60 related), member 2 NM_017305 Glutamate cysteine ligase, modifier subunit Gclm 4.59 NM_017309 Protein phospatase 3, regulatory subunit B, alpha Ppp3r1 4.54 isoform,type 1 NM_012765 5-hydroxytryptamine (serotonin) receptor 2C Htr2c 4.46 NM_017218 V-erb-b2 erythroblastic leukemia viral oncogene homolog Erbb3 4.42 3 (avian) AW918369 Zinc finger protein 191 Zfp191 4.38 NM_031034 Guanine nucleotide binding protein, alpha 12 Gna12 4.38 NM_017020 Interleukin 6 receptor Il6r 4.37 AJ002942 -
Inhibition of the MID1 Protein Complex
Matthes et al. Cell Death Discovery (2018) 4:4 DOI 10.1038/s41420-017-0003-8 Cell Death Discovery ARTICLE Open Access Inhibition of the MID1 protein complex: a novel approach targeting APP protein synthesis Frank Matthes1,MoritzM.Hettich1, Judith Schilling1, Diana Flores-Dominguez1, Nelli Blank1, Thomas Wiglenda2, Alexander Buntru2,HannaWolf1, Stephanie Weber1,InaVorberg 1, Alina Dagane2, Gunnar Dittmar2,3,ErichWanker2, Dan Ehninger1 and Sybille Krauss1 Abstract Alzheimer’s disease (AD) is characterized by two neuropathological hallmarks: senile plaques, which are composed of amyloid-β (Aβ) peptides, and neurofibrillary tangles, which are composed of hyperphosphorylated tau protein. Aβ peptides are derived from sequential proteolytic cleavage of the amyloid precursor protein (APP). In this study, we identified a so far unknown mode of regulation of APP protein synthesis involving the MID1 protein complex: MID1 binds to and regulates the translation of APP mRNA. The underlying mode of action of MID1 involves the mTOR pathway. Thus, inhibition of the MID1 complex reduces the APP protein level in cultures of primary neurons. Based on this, we used one compound that we discovered previously to interfere with the MID1 complex, metformin, for in vivo experiments. Indeed, long-term treatment with metformin decreased APP protein expression levels and consequently Aβ in an AD mouse model. Importantly, we have initiated the metformin treatment late in life, at a time-point where mice were in an already progressed state of the disease, and could observe an improved behavioral phenotype. These 1234567890 1234567890 findings together with our previous observation, showing that inhibition of the MID1 complex by metformin also decreases tau phosphorylation, make the MID1 complex a particularly interesting drug target for treating AD. -
Nck Adapter Proteins: Functional Versatility in T Cells Marcus Lettau, Jennifer Pieper and Ottmar Janssen
Cell Communication and Signaling BioMed Central Review Open Access Nck adapter proteins: functional versatility in T cells Marcus Lettau, Jennifer Pieper and Ottmar Janssen Address: 1University Hospital Schleswig-Holstein Campus Kiel, Institute of Immunology, Molecular Immunology, Arnold-Heller-Str 3, Bldg 17, D-24105 Kiel, Germany E-mail: Marcus Lettau* - [email protected]; Jennifer Pieper - [email protected]; Ottmar Janssen - [email protected] *Corresponding author Published: 02 February 2009 Received: 2 December 2008 Cell Communication and Signaling 2009, 7:1 doi: 10.1186/1478-811X-7-1 Accepted: 2 February 2009 This article is available from: http://www.biosignaling.com/content/7/1/1 © 2009 Lettau et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Nck is a ubiquitously expressed adapter protein that is almost exclusively built of one SH2 domain and three SH3 domains. The two isoproteins of Nck are functionally redundant in many aspects and differ in only few amino acids that are mostly located in the linker regions between the interaction modules. Nck proteins connect receptor and non-receptor tyrosine kinases to the machinery of actin reorganisation. Thereby, Nck regulates activation-dependent processes during cell polarisation and migration and plays a crucial role in the signal transduction of a variety of receptors including for instance PDGF-, HGF-, VEGF- and Ephrin receptors. In most cases, the SH2 domain mediates binding to the phosphorylated receptor or associated phosphoproteins, while SH3domaininteractionsleadtotheformationoflargerproteincomplexes.InTlymphocytes,Nck plays a pivotal role in the T cell receptor (TCR)-induced reorganisation of the actin cytoskeleton and the formation of the immunological synapse. -
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A Canonical Cancer-Network Map Eugene F. Douglass Jr., Ph.D. ;<=:>&'? Cell-Surface Interactions @@@JJ; Growth Receptor Signalling Cell-ECM Growth/Motility Proliferation Cell-Cell Contact Inhibition Metabolism MMP COLONIC CRYPT IGF/IGFR-1 EGFR / ErbB WNT ! WNT ! WNT WNT Integrin WNT RAS must be held near PI3K to activate it 5 CAD-domains Signalosome R-spdn p.195 GTP RAS PTEN NF1 SOS PLC PIP3 E-cadherin SHC PIP RASGAP GRB2 2 ZNRF3 p120 p120 " p120 p120 p120 p120 FZD Akt PDK1 PH JM Src-dep Y845 STAT3 GDP GTP Y974 F-actin PI3K PTB SHC/SHP2 GRB2 LRP Assembly vincilin talin PI3K Integrin-Linked Kinase(ILK) Y981 RAS RAS LGR RNF43 NCK2 ! ! ! ARP2/3 FAK Y988 FAK 2 min PINCH SOCS3 C hevell Akt KD s e paxilin SOS i d PDK1 Src IRS1 ! ! ! d paxilin Src (PKB) internlz AP2 RSU1 Y1015 ½ HIC5 ! t PI3K Y460 SOCS1/6 Y992 PLC" Parvin Src TESK1 PI3K Y546 SHIP2 GTP p130Cas CRK CSG ubiq axin PAK1 Y1091 Y1045 CBL S46-7 RAF-1 KSR DOCK180 SOS PI3K Y608 S1057 = GSK3 PI3K Y628 Y1127 Y1068 GRB2 14-3-3 14-3-3 PI3K Y658 GRB2 Y1086 B-RAF C-RAF GSK RHEB PI3K Y690 RASGAP 9 Wtx mTOR1 Y1163 Y1101 Gab1 Apc PI3K Y727 Y1167 PI3K Y759 RASGAP Y1168 MAPK Rac GTP Y1148 SHC GRB2 p120 p120 Y815 SHIP2 RhoGEF RalGEF p70-S6K Y1215 ! ! Y1175 SOS GTP Y891 phos SHP1 Cdc42 Y903 SHIP2 Y1253 SHP2 GRB2 ! ! PTP1 MKK1/2 PI3K Y935 Wtx GTP CT ! Rho PI3K Y983 SHIP2 Y1282 GRB2 SHP2 Y1006 Y1283 RalBP1 RalA/B GTP MP1 axin PI3K Y1352 PI3K Erk1/2 GSK3 Sprouty Apc MKP1 GTP GRB2 SHP2 Y1173 Rac 1. -
Transcriptome Analysis of Newt Lens Regeneration Reveals Distinct Gradients in Gene Expression Patterns
Transcriptome Analysis of Newt Lens Regeneration Reveals Distinct Gradients in Gene Expression Patterns Konstantinos Sousounis1., Mario Looso2., Nobuyasu Maki1¤, Clifford J. Ivester1, Thomas Braun3*, Panagiotis A. Tsonis1* 1 Department of Biology and Center for Tissue Regeneration and Engineering at Dayton, University of Dayton, Dayton, Ohio, United States of America, 2 Department of Bioinformatics, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany, 3 Department of Cardiac Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany Abstract Regeneration of the lens in newts is quite a unique process. The lens is removed in its entirety and regeneration ensues from the pigment epithelial cells of the dorsal iris via transdifferentiation. The same type of cells from the ventral iris are not capable of regenerating a lens. It is, thus, expected that differences between dorsal and ventral iris during the process of regeneration might provide important clues pertaining to the mechanism of regeneration. In this paper, we employed next generation RNA-seq to determine gene expression patterns during lens regeneration in Notophthalmus viridescens. The expression of more than 38,000 transcripts was compared between dorsal and ventral iris. Although very few genes were found to be dorsal- or ventral-specific, certain groups of genes were up-regulated specifically in the dorsal iris. These genes are involved in cell cycle, gene regulation, cytoskeleton and immune response. In addition, the expression of six highly regulated genes, TBX5, FGF10, UNC5B, VAX2, NR2F5, and NTN1, was verified using qRT-PCR. These graded gene expression patterns provide insight into the mechanism of lens regeneration, the markers that are specific to dorsal or ventral iris, and layout a map for future studies in the field.