DOCSLIB.ORG

The RET Receptor Is Linked to Stress Response Pathways

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The RET Receptor Is Linked to Stress Response Pathways [CANCER RESEARCH 64, 4453–4463, July 1, 2004] The RET Receptor Is Linked to Stress Response Pathways Shirley M. Myers and Lois M. Mulligan Division of Cancer Biology and Genetics, Queen’s Cancer Research Institute, Queen’s University, Kingston, Ontario, Canada ABSTRACT viewed in Ref. 13). Furthermore, rearrangements of RET, resulting in juxtaposition of the RET kinase domain with a dimerization domain RET is a transmembrane receptor required for the development of from any of several other proteins, occur somatically in papillary neuroendocrine and urogenital cell types. Activation of RET has roles in cell growth, migration, or differentiation, yet little is known about the gene thyroid carcinoma (14). In each case, these mutations result in acti- expression patterns through which these processes are mediated. We have vation of the RET receptor, leading to inappropriate and/or increased generated cell lines stably expressing either the RET9 or RET51 protein RET-mediated signal transduction and resultant cell proliferation and isoforms and have used these to investigate RET-mediated gene expres- tumorigenesis. sion patterns by cDNA microarray analyses. As seen for many oncogenes, Activation of RET, either by ligand or through specific mutations, we identified altered expression of genes associated generally with cell– results in phosphorylation of multiple tyrosine residues that, in turn, cell or cell-substrate interactions and up-regulation of tumor-specific interact with specific adaptor molecules to trigger downstream sig- transcripts. We also saw increased expression of transcripts normally naling. Four of the tyrosines phosphorylated on RET activation, associated with neural crest or other RET-expressing cell types, suggesting these genes may lie downstream of RET activation in development. The tyrosines 905, 1015, 1062, and 1096, have been well characterized, most striking pattern of expression was up-regulation of stress response and are known to interact with a number of adaptor molecules to genes. We showed that RET expression significantly up-regulated the stimulate signaling through phosphatidylinositol kinase (PI3K)/AKT, genes for heat shock protein (HSP) 70 family members, HSPA1A, PLC-␥, RAS/extracellular signal-regulated kinase (ERK), p38MAPK, HSPA1B, and HSPA1L. Other members of several HSP families and c-Jun NH2-terminal kinase (JNK), and ERK5 pathways (15–19). In HSP70-interacting molecules that were associated with stress response response to these signals, cell type-specific responses are initiated that protein complexes involved in protein maturation were also specifically implement the varied functional roles of RET. An additional level of up-regulated by RET, whereas those associated with the roles of HSP70 in protein degradation were down-regulated or unaffected. The major mech- complexity of RET signaling is added by alternative splicing of the anism of stress response induction is activation of the heat shock tran- RET gene (20), which leads to functionally distinct RET isoforms, scription factor HSF1. We showed that RET expression leads to increased termed RET9 and RET51. These isoforms differ in their COOH- HSF1 activation, which correlates with increased expression of stress terminal amino acids, having either 9 or 51 unique residues, and have response genes. Together, our data suggest that RET may be directly distinct transforming and differentiative potentials in vitro (21, 22). In responsible for expression of stress response proteins and the initiation of transgenic mice, animals expressing only the RET9 isoform are viable stress response. and appear normal, whereas monoisoformic RET51 animals have kidney dysplasia and lack enteric ganglia (23). These differences INTRODUCTION likely reflect differences in signaling potential of these RET isoforms. An additional phosphotyrosine, Y1096, present only in RET51, has The RET proto-oncogene encodes a receptor tyrosine kinase re- been shown to bind GRB2, activating PI3K and RAS/MAPK path- quired for normal development of the kidney, peripheral, and central ways (24–27). In addition, RET9 and RET51 differ in protein inter- nervous systems, and of spermatogonia (1–3). RET has been impli- actions with phosphotyrosine 1062, which is the last amino acid cated in cell type-specific processes including cell proliferation, mi- common to both isoforms and lies in different amino acid contexts in gration, and differentiation, and likely plays each of these roles in each protein (20). Tyrosine 1062 has been shown to act as a binding specific cells and at specific developmental time points. In neural cell site for multiple adaptor proteins including SHC, docking protein lineages, RET also plays an important role in cell survival, particu- (DOK)1, DOK4, DOK5, fibroblast growth factor receptor substrate 2 larly in response to environmental stresses (4–11). (FRS2), and insulin receptor substrate 1 (IRS1) (15, 26, 28–30); In normal cells, the RET receptor is activated by the binding of both however, the relative binding of these molecules to RET9 and to a circulating ligand and a cell surface-bound coreceptor. RET ligands RET51 varies both quantitatively and qualitatively. For example, SHC are members of the glial cell line-derived neurotrophic factor (GDNF) binds both RET9 and RET51 but, whereas RET51 binds only to the family (reviewed in Ref. 12). These molecules interact directly with SHC-PTB domain, RET9 can also bind through the SHC-SH2 domain coreceptors of the GDNF family receptors ␣ (GFR␣) proteins, which potentiating differences in the specific downstream interactions and/or are linked to the cell surface by glycosylphosphatidyl-inositol linkage, the magnitude of the signals transduced (26). and the resultant complexes bind to the RET receptor to activate Although many of the pathways through which RET transduces downstream signaling events. In addition, activating point mutations extracellular signals have been identified or predicted, little is known of RET have been identified in patients with multiple endocrine neoplasia type 2, an inherited cancer syndrome characterized by of the gene targets that are specifically modulated in response to medullary thyroid carcinoma and pheochromocytoma and are found receptor activation. In this study, we have used gene expression in a large proportion of sporadic medullary thyroid carcinoma (re- microarray analyses to evaluate targets of RET activation in an embryonic kidney-derived cell line. In addition to predictable targets involved in cell–cell interaction, cell proliferation, and neuroendo- Received 11/17/03; revised 3/17/04; accepted 4/30/04. Grant support: This work was supported by grants from the National Cancer Institute crine differentiation, our data suggest that activation of the RET of Canada and the Canadian Institutes of Health Research. receptor may specifically target genes for proteins integral to induc- The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with ible cellular stress response. This study may provide a direct link 18 U.S.C. Section 1734 solely to indicate this fact. between the up-regulation of heat shock proteins (HSPs), seen in Requests for reprints: Lois M. Mulligan, Queen’s Cancer Research Institute, Bot- terell Hall, Room 329, Queen’s University, Kingston, Ontario, Canada, K7L 3N6. Phone: many primary tumor types and as a neuroprotective event, and the (613) 533-6310; Fax: (613) 548-1348; E-mail: [email protected]. stimulation of receptor tyrosine kinase activity. 4453 Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 2004 American Association for Cancer Research. RET AND THE STRESS RESPONSE MATERIALS AND METHODS quence tags (ESTs) were obtained from the University Health Network Mi- croarray Centre. The EST content of the 1.7K array partially overlapped that Expression Constructs. Full-length human cDNAs encoding either the of the 19K array.1 Arrays were probed with differentially labeled cDNAs using 1072 amino acid (RET9) or the 1114 amino acid (RET51) isoforms of RET optimized protocols.2 Briefly, in a 40-␮l reaction, 10 ␮g of total RNA was (31) were cloned into CH269, an episomal expression vector derived from reverse transcribed using Superscript II according to the manufacturer’s in- vector pCEP4 (Invitrogen, Burlington, ON, Canada) under the control of the ␮ Ј Ј structions (Invitrogen) with 3.75 M Anchored-T primer (5 -T20VN-3 ); cytomegalovirus promoter. The sequence of each construct was verified by dATP, dGTP, and dTTP (500 ␮M each); and 50 ␮M dCTP, 10 mM DTT, 1 ng restriction digestion, and direct sequencing (Mobix, Hamilton, ON, Canada). of control RNA (artificial Arabadopsis transcripts), and either 25 ␮M Cy3- The GFR␣1 expression construct has been described previously (32, 33). dCTP or Cy5-dCTP (Mandel-NEN, Guelph, ON, Canada) at 42°C for 2–3h. Cell Culture and Transfection Experiments. E293, a transformed em- RNA was hydrolized and Cy5 and Cy3-labeled cDNA were combined, iso- bryonic kidney cell line, was maintained in DMEM, supplemented with 10% propanol precipitated, and resuspended in water. Labeled cDNAs were hybrid- fetal bovine serum, penicillin, streptomycin, and G418. For transient transfec- ized to cDNA microarrays in a medium consisting of DIG Easy Hyb solution tions, E293 cells were seeded into six-well plates and grown to approximately (Roche Applied Science, Laval, QC, Canada) containing 50 ␮g of yeast tRNA 70–80%
Load more

Recommended publications
  • Deletion of Endoplasmic Reticulum Stress-Responsive Co-Chaperone P58ipk Protects Mice from Diet-Induced Steatohepatitis
    Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2018 Deletion of endoplasmic reticulum stress-responsive co-chaperone p58IPK protects mice from diet-induced steatohepatitis Bandla, Harikrishna ; Dasgupta, Debanjali ; Mauer, Amy S ; Nozickova, Barbora ; Kumar, Swarup ; Hirsova, Petra ; Graham, Rondell P ; Malhi, Harmeet DOI: https://doi.org/10.1111/hepr.13052 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-144890 Journal Article Accepted Version Originally published at: Bandla, Harikrishna; Dasgupta, Debanjali; Mauer, Amy S; Nozickova, Barbora; Kumar, Swarup; Hirsova, Petra; Graham, Rondell P; Malhi, Harmeet (2018). Deletion of endoplasmic reticulum stress-responsive co-chaperone p58IPK protects mice from diet-induced steatohepatitis. Hepatology Research, 48(6):479- 494. DOI: https://doi.org/10.1111/hepr.13052 Deletion of endoplasmic reticulum stress-responsive co-chaperone p58IPK protects mice from diet-induced steatohepatitis Harikrishna Bandla1, Debanjali Dasgupta1, Amy S. Mauer1, Barbora Nozickova2, Swarup Kumar3, Petra Hirsova1, Rondell P. Graham4, Harmeet Malhi1* 1. Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 2. Universitatsspital Zurich, 8096, Ramistrasse 100, Zurich, Switzerland 3. Department of Medicine, Saint Vincent Hospital, 123 Summer St, Worcester, MA 4. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN Corresponding author: Harmeet Malhi, M.B.B.S. Associate Professor of Medicine and Physiology Mayo Clinic College of Medicine 200 First Street SW Rochester, MN 55905 Tel: 507 284 0686 Fax: 507 284 0762 Email: [email protected] Funding: This work was supported by DK 97178, DK107402 and DK111378 (H.M.), the Robert and Elizabeth Strickland Career Development Award from the Division of Endocrinology (H.M.), the Gilead Sciences Research Scholars Program in Liver Disease (H.M.) and the Palumbo Foundation (H.M.), the Edward C.
    [Show full text]
  • Nuclear and Mitochondrial Genome Defects in Autisms
    UC Irvine UC Irvine Previously Published Works Title Nuclear and mitochondrial genome defects in autisms. Permalink https://escholarship.org/uc/item/8vq3278q Journal Annals of the New York Academy of Sciences, 1151(1) ISSN 0077-8923 Authors Smith, Moyra Spence, M Anne Flodman, Pamela Publication Date 2009 DOI 10.1111/j.1749-6632.2008.03571.x License https://creativecommons.org/licenses/by/4.0/ 4.0 Peer reviewed eScholarship.org Powered by the California Digital Library University of California THE YEAR IN HUMAN AND MEDICAL GENETICS 2009 Nuclear and Mitochondrial Genome Defects in Autisms Moyra Smith, M. Anne Spence, and Pamela Flodman Department of Pediatrics, University of California, Irvine, California In this review we will evaluate evidence that altered gene dosage and structure im- pacts neurodevelopment and neural connectivity through deleterious effects on synap- tic structure and function, and evidence that the latter are key contributors to the risk for autism. We will review information on alterations of structure of mitochondrial DNA and abnormal mitochondrial function in autism and indications that interactions of the nuclear and mitochondrial genomes may play a role in autism pathogenesis. In a final section we will present data derived using Affymetrixtm SNP 6.0 microar- ray analysis of DNA of a number of subjects and parents recruited to our autism spectrum disorders project. We include data on two sets of monozygotic twins. Col- lectively these data provide additional evidence of nuclear and mitochondrial genome imbalance in autism and evidence of specific candidate genes in autism. We present data on dosage changes in genes that map on the X chromosomes and the Y chro- mosome.
    [Show full text]
  • Computational Genome-Wide Identification of Heat Shock Protein Genes in the Bovine Genome [Version 1; Peer Review: 2 Approved, 1 Approved with Reservations]
    F1000Research 2018, 7:1504 Last updated: 08 AUG 2021 RESEARCH ARTICLE Computational genome-wide identification of heat shock protein genes in the bovine genome [version 1; peer review: 2 approved, 1 approved with reservations] Oyeyemi O. Ajayi1,2, Sunday O. Peters3, Marcos De Donato2,4, Sunday O. Sowande5, Fidalis D.N. Mujibi6, Olanrewaju B. Morenikeji2,7, Bolaji N. Thomas 8, Matthew A. Adeleke 9, Ikhide G. Imumorin2,10,11 1Department of Animal Breeding and Genetics, Federal University of Agriculture, Abeokuta, Nigeria 2International Programs, College of Agriculture and Life Sciences, Cornell University, Ithaca, NY, 14853, USA 3Department of Animal Science, Berry College, Mount Berry, GA, 30149, USA 4Departamento Regional de Bioingenierias, Tecnologico de Monterrey, Escuela de Ingenieria y Ciencias, Queretaro, Mexico 5Department of Animal Production and Health, Federal University of Agriculture, Abeokuta, Nigeria 6Usomi Limited, Nairobi, Kenya 7Department of Animal Production and Health, Federal University of Technology, Akure, Nigeria 8Department of Biomedical Sciences, Rochester Institute of Technology, Rochester, NY, 14623, USA 9School of Life Sciences, University of KwaZulu-Natal, Durban, 4000, South Africa 10School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, 30032, USA 11African Institute of Bioscience Research and Training, Ibadan, Nigeria v1 First published: 20 Sep 2018, 7:1504 Open Peer Review https://doi.org/10.12688/f1000research.16058.1 Latest published: 20 Sep 2018, 7:1504 https://doi.org/10.12688/f1000research.16058.1 Reviewer Status Invited Reviewers Abstract Background: Heat shock proteins (HSPs) are molecular chaperones 1 2 3 known to bind and sequester client proteins under stress. Methods: To identify and better understand some of these proteins, version 1 we carried out a computational genome-wide survey of the bovine 20 Sep 2018 report report report genome.
    [Show full text]
  • Epha Receptors and Ephrin-A Ligands Are Upregulated by Monocytic
    Mukai et al. BMC Cell Biology (2017) 18:28 DOI 10.1186/s12860-017-0144-x RESEARCHARTICLE Open Access EphA receptors and ephrin-A ligands are upregulated by monocytic differentiation/ maturation and promote cell adhesion and protrusion formation in HL60 monocytes Midori Mukai, Norihiko Suruga, Noritaka Saeki and Kazushige Ogawa* Abstract Background: Eph signaling is known to induce contrasting cell behaviors such as promoting and inhibiting cell adhesion/ spreading by altering F-actin organization and influencing integrin activities. We have previously demonstrated that EphA2 stimulation by ephrin-A1 promotes cell adhesion through interaction with integrins and integrin ligands in two monocyte/ macrophage cell lines. Although mature mononuclear leukocytes express several members of the EphA/ephrin-A subclass, their expression has not been examined in monocytes undergoing during differentiation and maturation. Results: Using RT-PCR, we have shown that EphA2, ephrin-A1, and ephrin-A2 expression was upregulated in murine bone marrow mononuclear cells during monocyte maturation. Moreover, EphA2 and EphA4 expression was induced, and ephrin-A4 expression was upregulated, in a human promyelocytic leukemia cell line, HL60, along with monocyte differentiation toward the classical CD14++CD16− monocyte subset. Using RT-PCR and flow cytometry, we have also shown that expression levels of αL, αM, αX, and β2 integrin subunits were upregulated in HL60 cells along with monocyte differentiation while those of α4, α5, α6, and β1 subunits were unchanged. Using a cell attachment stripe assay, we have shown that stimulation by EphA as well as ephrin-A, likely promoted adhesion to an integrin ligand- coated surface in HL60 monocytes. Moreover, EphA and ephrin-A stimulation likely promoted the formation of protrusions in HL60 monocytes.
    [Show full text]
  • C-Terminal HSP90 Inhibitors Block the HSP90:HIF-1Α Interaction and Inhibit the Cellular Hypoxic Response
    bioRxiv preprint doi: https://doi.org/10.1101/521989; this version posted January 24, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. C-terminal HSP90 Inhibitors Block the HSP90:HIF-1α Interaction and Inhibit the Cellular Hypoxic Response Nalin Katariaa, Bernadette Kerra, Samantha S. Zaiterb, Shelli McAlpineb and Kristina M Cooka† a. University of Sydney, Faculty of Medicine and Health, Charles Perkins Centre, Sydney, Australia. b. School of Chemistry, University of New South Wales, Sydney, Australia. † To whom correspondence should be addressed: Kristina M Cook, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia 2006; [email protected]; Tel: +61 286274858. Hypoxia Inducible Factor (HIF) is a transcription factor cancer cells known as a heat shock response (HSR)12. The activated by low oxygen, which is common in solid compounds also have poor selectivity for HSP9013,14. tumours. HIF controls the expression of genes involved in C-terminus inhibitors of HSP90 (SM molecules)11 act in a angiogenesis, chemotherapy resistance and metastasis. The selective manner, and in contrast to the N-terminus chaperone HSP90 (Heat Shock Protein 90) stabilizes the inhibitors, they do not induce a heat shock response13,15. subunit HIF-1α and prevents degradation. Previously Although the SM molecules block all co-chaperones that identified HSP90 inhibitors bind to the N-terminal pocket bind to the C-terminus of HSP90 and inhibit HSP90 of HSP90 which blocks binding to HIF-1α, and produces function16,17, there is no data discussing whether C- HIF-1α degradation.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • The Intrinsically Disordered Proteins of Myelin in Health and Disease
    cells Review Flexible Players within the Sheaths: The Intrinsically Disordered Proteins of Myelin in Health and Disease Arne Raasakka 1 and Petri Kursula 1,2,* 1 Department of Biomedicine, University of Bergen, Jonas Lies vei 91, NO-5009 Bergen, Norway; [email protected] 2 Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, Aapistie 7A, FI-90220 Oulu, Finland * Correspondence: [email protected] Received: 30 January 2020; Accepted: 16 February 2020; Published: 18 February 2020 Abstract: Myelin ensheathes selected axonal segments within the nervous system, resulting primarily in nerve impulse acceleration, as well as mechanical and trophic support for neurons. In the central and peripheral nervous systems, various proteins that contribute to the formation and stability of myelin are present, which also harbor pathophysiological roles in myelin disease. Many myelin proteins have common attributes, including small size, hydrophobic segments, multifunctionality, longevity, and regions of intrinsic disorder. With recent advances in protein biophysical characterization and bioinformatics, it has become evident that intrinsically disordered proteins (IDPs) are abundant in myelin, and their flexible nature enables multifunctionality. Here, we review known myelin IDPs, their conservation, molecular characteristics and functions, and their disease relevance, along with open questions and speculations. We place emphasis on classifying the molecular details of IDPs in myelin, and we correlate these with their various functions, including susceptibility to post-translational modifications, function in protein–protein and protein–membrane interactions, as well as their role as extended entropic chains. We discuss how myelin pathology can relate to IDPs and which molecular factors are potentially involved. Keywords: myelin; intrinsically disordered protein; multiple sclerosis; peripheral neuropathies; myelination; protein folding; protein–membrane interaction; protein–protein interaction 1.
    [Show full text]
  • Crosstalk Between Integrin and Receptor Tyrosine Kinase Signaling in Breast Carcinoma Progression
    BMB reports Mini Review Crosstalk between integrin and receptor tyrosine kinase signaling in breast carcinoma progression Young Hwa Soung, John L. Clifford & Jun Chung* Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130 This review explored the mechanism of breast carcinoma pro- cancer originates from breast epithelial cells that are trans- gression by focusing on integrins and receptor tyrosine kinases formed into metastatic carcinomas. Metastatic potential and re- (or growth factor receptors). While the primary role of integrins sponsiveness to treatment vary depending on the expression of was previously thought to be solely as mediators of adhesive hormone receptors such as estrogen receptor and progesterone interactions between cells and extracellular matrices, it is now receptor (5), RTKs such as ErbB-2, epidermal growth factor re- believed that integrins also regulate signaling pathways that ceptor (EGFR), and hepatocyte growth factor receptor, c-Met control cancer cell growth, survival, and invasion. A large (6), and integrins (7). Major integrins expressed on breast epi- body of evidence suggests that the cooperation between in- thelial cells include α2β1, α3β1, αvβ3, αvβ5, αvβ6, α5β1, tegrin and receptor tyrosine kinase signaling regulates certain α6β1, and α6β4 (7). Among these, this review focuses on signaling functions that are important for cancer progression. αvβ3, α5β1, and α6β4, all of which are upregulated in in- Recent developments on the crosstalk between integrins and vasive breast carcinoma and have well established relation- receptor tyrosine kinases, and its implication in mammary tu- ships with RTKs (8). These integrins serve as receptors for vi- mor progression, are discussed.
    [Show full text]
  • Holdase Activity of Secreted Hsp70 Masks Amyloid-Β42 Neurotoxicity in Drosophila
    Holdase activity of secreted Hsp70 masks amyloid-β42 neurotoxicity in Drosophila Pedro Fernandez-Funeza,b,c,1, Jonatan Sanchez-Garciaa, Lorena de Menaa, Yan Zhanga, Yona Levitesb, Swati Kharea, Todd E. Goldea,b, and Diego E. Rincon-Limasa,b,c,1 aDepartment of Neurology, McKnight Brain Institute, University of Florida, Gainesville, FL 32611; bDepartment of Neuroscience, Center for Translational Research on Neurodegenerative Diseases, University of Florida, Gainesville, FL 32611; and cGenetics Institute, University of Florida, Gainesville, FL 32611 Edited by Nancy M. Bonini, University of Pennsylvania, Philadelphia, PA, and approved July 11, 2016 (received for review May 25, 2016) Alzheimer’s disease (AD) is the most prevalent of a large group of cell-free systems by dissociating preformed oligomers but not fi- related proteinopathies for which there is currently no cure. Here, we brils, suggesting that Hsp70 targets oligomeric intermediates (18). used Drosophila to explore a strategy to block Aβ42 neurotoxicity More recent in vitro studies show that Hsp70 and other chaperones through engineering of the Heat shock protein 70 (Hsp70), a chap- promote the aggregation of oligomers into less toxic species (19). erone that has demonstrated neuroprotective activity against several Also, Hsp70 demonstrates neuroprotection against intracellular intracellular amyloids. To target its protective activity against extra- Aβ42 in primary cultures (20), whereas down-regulation of Hsp70 cellular Aβ42, we added a signal peptide to Hsp70. This secreted form leads to increased protein aggregation in transgenic worms of Hsp70 (secHsp70) suppresses Aβ42 neurotoxicity in adult eyes, expressing intracellular Aβ42 (21). A recent study in a transgenic reduces cell death, protects the structural integrity of adult neurons, mouse model of AD overexpressing the Amyloid precursor pro- alleviates locomotor dysfunction, and extends lifespan.
    [Show full text]
  • At Elevated Temperatures, Heat Shock Protein Genes Show Altered Ratios Of
    EXPERIMENTAL AND THERAPEUTIC MEDICINE 22: 900, 2021 At elevated temperatures, heat shock protein genes show altered ratios of different RNAs and expression of new RNAs, including several novel HSPB1 mRNAs encoding HSP27 protein isoforms XIA GAO1,2, KEYIN ZHANG1,2, HAIYAN ZHOU3, LUCAS ZELLMER4, CHENGFU YUAN5, HAI HUANG6 and DEZHONG JOSHUA LIAO2,6 1Department of Pathology, Guizhou Medical University Hospital; 2Key Lab of Endemic and Ethnic Diseases of The Ministry of Education of China in Guizhou Medical University; 3Clinical Research Center, Guizhou Medical University Hospital, Guiyang, Guizhou 550004, P.R. China; 4Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; 5Department of Biochemistry, China Three Gorges University, Yichang, Hubei 443002; 6Center for Clinical Laboratories, Guizhou Medical University Hospital, Guiyang, Guizhou 550004, P.R. China Received December 16, 2020; Accepted May 10, 2021 DOI: 10.3892/etm.2021.10332 Abstract. Heat shock proteins (HSP) serve as chaperones genes may engender multiple protein isoforms. These results to maintain the physiological conformation and function of collectively suggested that, besides increasing their expres‑ numerous cellular proteins when the ambient temperature is sion, certain HSP and associated genes also use alternative increased. To determine how accurate the general assumption transcription start sites to produce multiple RNA transcripts that HSP gene expression is increased in febrile situations is, and use alternative splicing of a transcript to produce multiple the RNA levels of the HSF1 (heat shock transcription factor 1) mature RNAs, as important mechanisms for responding to an gene and certain HSP genes were determined in three cell increased ambient temperature in vitro. lines cultured at 37˚C or 39˚C for three days.
    [Show full text]
  • Targeting PH Domain Proteins for Cancer Therapy
    The Texas Medical Center Library DigitalCommons@TMC The University of Texas MD Anderson Cancer Center UTHealth Graduate School of The University of Texas MD Anderson Cancer Biomedical Sciences Dissertations and Theses Center UTHealth Graduate School of (Open Access) Biomedical Sciences 12-2018 Targeting PH domain proteins for cancer therapy Zhi Tan Follow this and additional works at: https://digitalcommons.library.tmc.edu/utgsbs_dissertations Part of the Bioinformatics Commons, Medicinal Chemistry and Pharmaceutics Commons, Neoplasms Commons, and the Pharmacology Commons Recommended Citation Tan, Zhi, "Targeting PH domain proteins for cancer therapy" (2018). The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access). 910. https://digitalcommons.library.tmc.edu/utgsbs_dissertations/910 This Dissertation (PhD) is brought to you for free and open access by the The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences at DigitalCommons@TMC. It has been accepted for inclusion in The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access) by an authorized administrator of DigitalCommons@TMC. For more information, please contact [email protected]. TARGETING PH DOMAIN PROTEINS FOR CANCER THERAPY by Zhi Tan Approval page APPROVED: _____________________________________________ Advisory Professor, Shuxing Zhang, Ph.D. _____________________________________________
    [Show full text]
  • The Roma Paradigm
    The Counteracting Effects of Demography on Functional Genomic Variation: The Roma Paradigm Neus Font-Porterias,1 Rocio Caro-Consuegra,1 Marcel Lucas-Sanchez,1 Marie Lopez,2 Aaron Gimenez,3 Annabel Carballo-Mesa,4 Elena Bosch,1,5 Francesc Calafell ,1 Lluıs Quintana-Murci,2,6 and David Comas *,1 Downloaded from https://academic.oup.com/mbe/article/38/7/2804/6169539 by Consejo Superior de Investigaciones Cientificas (CSIC) user on 31 August 2021 1Departament de Cie`ncies Experimentals i de la Salut, Institut de Biologia Evolutiva (UPF-CSIC), Universitat Pompeu Fabra, Barcelona, Spain 2Human Evolutionary Genetics Unit, Institut Pasteur, UMR2000, CNRS, Paris, France 3Facultat de Sociologia, Universitat Autonoma de Barcelona, Barcelona, Spain 4Facultat de Geografia i Historia, Universitat de Barcelona, Barcelona, Spain 5Centro de Investigacion Biomedica en Red de Salud Mental (CIBERSAM), Reus, Spain 6Human Genomics and Evolution, Colle`gedeFrance,Paris,France *Corresponding author: E-mail: [email protected]. Associate editor: Kelley Harris Abstract Demographic history plays a major role in shaping the distribution of genomic variation. Yet the interaction between different demographic forces and their effects in the genomesisnotfullyresolvedinhumanpopulations. Here, we focus on the Roma population, the largest transnational ethnic minority in Europe. They have a South Asian origin and their demographic history is characterized by recent dispersals, multiple founder events, and extensive gene flow from non- Roma groups. Through the analyses of new high-coverage whole exome sequences and genome-wide array data for 89 Iberian Roma individuals together with forward simulations, we show that founder effects have reduced their genetic diversity and proportion of rare variants, gene flow has counteracted the increase in mutational load, runs of homo- zygosity show ancestry-specific patterns of accumulation of deleterious homozygotes, and selection signals primarily derive from preadmixture adaptation in the Roma population sources.
    [Show full text]