DOCSLIB.ORG

Effect of the Large and Small T-Antigens of Human Polyomaviruses on Signaling Pathways

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Effect of the Large and Small T-Antigens of Human Polyomaviruses on Signaling Pathways International Journal of Molecular Sciences Review Effect of the Large and Small T-Antigens of Human Polyomaviruses on Signaling Pathways Ugo Moens 1,* and Andrew Macdonald 2,* 1 Molecular Inflammation Research Group, Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, 9019 Tromsø, Norway 2 School of Molecular and Cellular Biology, Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK * Correspondence: [email protected] (U.M.); [email protected] (A.M.) Received: 22 July 2019; Accepted: 10 August 2019; Published: 12 August 2019 Abstract: Viruses are intracellular parasites that require a permissive host cell to express the viral genome and to produce new progeny virus particles. However, not all viral infections are productive and some viruses can induce carcinogenesis. Irrespective of the type of infection (productive or neoplastic), viruses hijack the host cell machinery to permit optimal viral replication or to transform the infected cell into a tumor cell. One mechanism viruses employ to reprogram the host cell is through interference with signaling pathways. Polyomaviruses are naked, double-stranded DNA viruses whose genome encodes the regulatory proteins large T-antigen and small t-antigen, and structural proteins that form the capsid. The large T-antigens and small t-antigens can interfere with several host signaling pathways. In this case, we review the interplay between the large T-antigens and small t-antigens with host signaling pathways and the biological consequences of these interactions. Keywords: apoptosis; DNA damage response; immune response; interferon; MAP kinase; NFκB; p53; PI3K; protein phosphatases; retinoblastoma 1. Introduction The Polyomaviridae family consists of naked viruses with an icosahedral capsid structure. Although originally isolated in mammals, polyomaviruses (PyV) also infect birds and, recently, PyV sequences have also been detected in insects, fish, amphibians, and reptiles. However, it remains to be established whether PyV can actually infect these species [1,2]. The circular double-stranded DNA genome of PyV encodes regulatory and structural proteins, which are expressed in a time-dependent fashion. The regulatory proteins are expressed before the onset of viral DNA replication and are referred to as the early proteins, whereas the structural proteins are synthesized later in the infection cycle and, therefore, are called the late proteins. The early proteins are required for viral DNA replication and transcription, while the late proteins form the capsid [2]. So far, 14 different human polyomaviruses (HPyV) have been described. BKPyV and JCPyV were the first HPyV to be isolated in 1971 and they were named after the initials of the patient [3,4]. In the last decade, 12 novel HPyV have been described: KIPyV [5], WUPyV [6], Merkel cell polyomavirus (MCPyV; [7]), HPyV6 [8], HPyV7 [8], Trichodysplasia spinulosa-associated polyomavirus (TSPyV; [9]), HPyV9 [10], MWPyV [11,12], STLPyV [13], HPyV12 [14], NJPyV [15], and LIPyV [16]. They all encode at least two early proteins: large T-antigen (LT) and small t-antigen (sT), but other early proteins have been detected or may be encoded by the viral genome (Figure1). Most HPyV produce three late proteins: VP1, VP2, and VP3. BKPyV and JCPyV encode an additional non-structural late protein known as the agnoprotein [17], whereas MCPyV does not seem to express VP3 [18]. HPyV infection is common in the human population. Serological studies have shown a seroprevalence ranging from Int. J. Mol. Sci. 2019, 20, 3914; doi:10.3390/ijms20163914 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2019, 20, 3914 2 of 34 Int. J. Mol. Sci. 2019, 20, x FOR PEER REVIEW 2 of 34 ~5%seroprevalence for HPyV12, ranging NJPyV, from and ~5% LIPyV, for HPyV12, ~20% for NJPyV, HPyV9 and and LIPyV,60% for~20% the for other HPyV9 HPyV and in ≥ the60% healthy for the ≥ adultother population.HPyV in the Moreover, healthy eachadult individual population is. infected Moreover, with each several individual HPyVs [19is ,20infected]. Primary with infection several occursHPyVs in[19,20 early]. childhood,Primary infection after which occur thes in virus early establishes childhood, aafter life-long which and the sub-clinical virus establishes co-existence a life- withlong itsand host [21sub].- Immunodeficientclinical co-existence conditions, with immunosuppressive its host [21]. drugs,Immunodeficient and pregnancy conditions, can lead to reactivationimmunosuppressive of HPyV anddrugs may, and cause pregnancy diseases. can BKPyV lead to causes reactivation polyomavirus-associated of HPyV and may nephropathycause diseases. in renalBKPyV transplant causes polyomavirus patients and hemorrhagic-associated cystitisnephropathy in bone in marrow renal transplant transplants. patients JCPyV and is associated hemorrhagic with progressivecystitis in multifocalbone marrow leukoencephalopathy transplants. andJCPyV TSPyV is isassociated linked to trichodysplasiawith progressive spinulosa, multifocal which isleukoencephalopathy a rare skin disease of and severely TSPyV immunocompromised is linked to trichodysplasia hosts characterized spinulosa, which by follicular is a rare distention skin disease and keratoticof severely spine immunocompromised formation [22,23]. Despite hosts theircharacterized name (poly by= follicularmany and distention oma = cancers), and keratotic MCPyV seemsspine toformation be the only [22,23] HPyV. Despite to induce their cancername ( inpol itsy = natural many and host. oma MCPyV = cancers is a) major, MCPyV cause seem in thes to skinbe the cancer only calledHPyV Merkelto induce cell cancer carcinoma in its [natural7,24]. The host. role MCPyV of other is HPyV,a major especially cause in BKPyVthe skin and cancer JCPyV, called in humanMerkel cancercell carcinoma such as [7 prostate,,24]. The colorectal, role of other urothelial, HPyV, especially and brain BKPyV cancer and is disputed JCPyV, in (for human recent cancer reviews, such see as Referencesprostate, colorectal, [25–29]), urothelial, but some ofand them brain can cancer transform is disputed cells, including (for recent human reviews cells,, see and References the virus [25 or– its29] early), but proteinssome of them LT or can/and transform sT can cause cells, tumors including in animalhuman modelscells, and [27 the,28 ,virus30]. HPyV6or its early and proteins HPyV7 mayLT or/and be associated sT can cause with atumors pruritic in rash animal [31, 32models], while, [27 so,28 far,,30] no. HPyV6 diseases and have HPyV been7 may associated be associate for thed otherwith a HPyV. pruritic rash [31,32], while, so far, no diseases have been associated for the other HPyV. Figure 1.1. ProvenProven and and putative putative early early proteins proteins are are encoded by by the different different HPyV. The numbernumber in parenthesis isis the the number number of of amino amino acid acid residues residues in the in protein.the protein. The dashedThe dashed lines representlines represent non-coding non- regions,coding regions, while thewhile colored the colored boxes boxes depict depict the distinct the distinct areas areas that that compose compose the the protein. protein. Part Part ofof the N-terminalN-terminal region of of LT LT and and sT sT ha hass the the same same amino amino acid acid sequence sequence and and,, therefore therefore,, the same the same color color was wasused. used. The proteins The proteins are not are drawn not drawn to exact to exactscale. scale. LT = large LT = largeT-antigen T-antigen.. sT = small sT = Tsmall-antigen T-antigen.. MT = MTmiddle= middle T-antigen T-antigen.. ALTO ALTO = alternative= alternative LT open LT reading open reading frame. frame. Viruses, includingincluding polyomaviruses, recruit the host cell machinery to favour their replication, and,and, in thethe casecase ofof oncoviruses,oncoviruses, toto causecause carcinogenesis.carcinogenesis. One way to take control or perturb cellular processes is byby interferinginterfering with signaling pathways regulating processesprocesses such as DNA replication, the cellcell cycle, cycle, the the immune immune response, response, transcription, transcription, metabolism, metabolism, DNA DNA repair, repair, cell survival, cell survival, cell motility, cell Int. J. Mol. Sci. 2019, 20, 3914 3 of 34 and angiogenesis [33–37]. In the next sections, we review the different pathways that are affected by HPyV and discuss the biological relevance of these interactions. 2. Interaction Partners of HPyV LT and sT One way to explore the impact of HPyV on signaling pathways is to identify which cellular proteins can bind to LT and sT. Several methods such as co-immunoprecipitation, tandem affinity purification coupled to mass spectrometry, GST pull down of in vitro translated proteins, stable isotope labeling by amino acids in cell culture (SILAC)-based pull down, and yeast two-hybrid have been used to identify cellular interaction partners of HPyV LT and sT to understand the function of these proteins [2]. A list of cellular proteins that interact with HPyV LT and sT is given in Table1. Some of these proteins are part of signaling pathways and will be discussed in Section3. A special group of proteins that are targeted by HPyV are the protein phosphatases. Because protein phosphatases can interfere with several signaling pathways and targeting them is one of the strategies polyomaviruses use to optimize the host cell for their replication or to transform
Load more

Recommended publications
  • Thesis Template
    Functional and Structural Characterization Reveals Novel FBXW7 Biology by Tonny Chao Huang A thesis submitted in conformity with the requirements for the degree of Master of Science Department of Medical Biophysics University of Toronto © Copyright by Tonny Chao Huang 2018 Functional and Structural Characterization Reveals Novel FBXW7 Biology Tonny Chao Huang Master of Science Department of Medical Biophysics University of Toronto 2018 Abstract This thesis aims to examine aspects of FBXW7 biology, a protein that is frequently mutated in a variety of cancers. The first part of this thesis describes the characterization of FBXW7 isoform and mutant substrate profiles using a proximity-dependent biotinylation assay. Isoform-specific substrates were validated, revealing the involvement of FBXW7 in the regulation of several protein complexes. Characterization of FBXW7 mutants also revealed site- and residue-specific consequences on the binding of substrates and, surprisingly, possible neo-substrates. In the second part of this thesis, we utilize high-throughput peptide binding assays and statistical modelling to discover novel features of the FBXW7-binding phosphodegron. In contrast to the canonical motif, a possible preference of FBXW7 for arginine residues at the +4 position was discovered. I then attempted to validate this feature in vivo and in vitro on a novel substrate discovered through BioID. ii Acknowledgments The past three years in the Department of Medical Biophysics have defied expectations. I not only had the opportunity to conduct my own independent research, but also to work with distinguished collaborators and to explore exciting complementary fields. I experienced the freedom to guide my own academic development, as well as to pursue my extracurricular interests.
    [Show full text]
  • Enhanced Expression of Vascular Endothelial Growth Factor (VEGF) Plays a Critical Role in the Tumor Progression Potential Induced by Simian Virus 40 Large T Antigen
    Oncogene (2002) 21, 2896 ± 2900 ã 2002 Nature Publishing Group All rights reserved 0950 ± 9232/02 $25.00 www.nature.com/onc Enhanced expression of vascular endothelial growth factor (VEGF) plays a critical role in the tumor progression potential induced by simian virus 40 large T antigen Alfonso Catalano1, Mario Romano*,2, Stefano Martinotti3 and Antonio Procopio*,1 1Institute of Experimental Pathology, University of Ancona, Faculty of Medicine, Via Ranieri, 60131 Ancona, Italy; 2Department of Human Pathology, University of Messina, 98125 Messina, Italy; 3Department of Oncology and Neuroscience, `G. D'Annunzio' University, Chieti, Italy Vascular endothelial growth factor (VEGF), an impor- disorders, including mesotheliomas (Kumar-Singh et tant angiogenic factor, regulates cell proliferation, al., 1999). Among these, VEGF, whose crucial role in dierentiation, and apoptosis through activation of its tumor angiogenesis is well established (Hanahan and tyrosine-kinase receptors, such as Flt-1 and Flk-1/Kdr. Folkman., 1996), acts also as a potent mitogen and Human malignant mesothelioma cells (HMC), which survival factor for human malignant mesothelioma have wild-type p53, express VEGF and exhibit cell cells (HMC). In fact, VEGF regulates HMC prolifera- growth increased by VEGF. Here, we demonstrate that tion through its tyrosine-kinase receptors activation early transforming proteins of simian virus (SV) 40, large (i.e. Flt-1 and KDR/¯k-1) (Strizzi et al., 2001). In tumor antigen (Tag) and small tumor antigen (tag), addition, VEGF is the main eector of 5-lipoxygenase which have been associated with mesotheliomas, en- action on HMC survival (Romano et al., 2001). Thus, hanced HMC proliferation by inducing VEGF expres- VEGF plays a key role by regulating multiple sion.
    [Show full text]
  • Repression of Viral Gene Expression and Replication by the Unfolded Protein Response Effector Xbp1u Florian Hinte1, Eelco Van Anken2,3, Boaz Tirosh4, Wolfram Brune1*
    RESEARCH ARTICLE Repression of viral gene expression and replication by the unfolded protein response effector XBP1u Florian Hinte1, Eelco van Anken2,3, Boaz Tirosh4, Wolfram Brune1* 1Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany; 2Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy; 3Universita` Vita-Salute San Raffaele, Milan, Italy; 4Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel Abstract The unfolded protein response (UPR) is a cellular homeostatic circuit regulating protein synthesis and processing in the ER by three ER-to-nucleus signaling pathways. One pathway is triggered by the inositol-requiring enzyme 1 (IRE1), which splices the X-box binding protein 1 (Xbp1) mRNA, thereby enabling expression of XBP1s. Another UPR pathway activates the activating transcription factor 6 (ATF6). Here we show that murine cytomegalovirus (MCMV), a prototypic b-herpesvirus, harnesses the UPR to regulate its own life cycle. MCMV activates the IRE1-XBP1 pathway early post infection to relieve repression by XBP1u, the product of the unspliced Xbp1 mRNA. XBP1u inhibits viral gene expression and replication by blocking the activation of the viral major immediate-early promoter by XBP1s and ATF6. These findings reveal a redundant function of XBP1s and ATF6 as activators of the viral life cycle, and an unexpected role of XBP1u as a potent repressor of both XBP1s and ATF6-mediated activation. *For correspondence: [email protected] Introduction The endoplasmic reticulum (ER) is responsible for synthesis, posttranslational modification, and fold- Competing interest: See ing of a substantial portion of cellular proteins.
    [Show full text]
  • Oncogenes of DNA Tumor Viruses1
    [CANCER RESEARCH 48. 493-496. February I. 1988] Perspectives in Cancer Research Oncogenes of DNA Tumor Viruses1 Arnold J. Levine Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544 Experiments carried out over the past 10-12 years have the cellular oncogenes. It will attempt to identify where more created a field or approach which may properly be termed the information is required or contradictions appear in the devel molecular basis of cancer. One of its major accomplishments oping concepts. Finally, this communication will examine ex has been the identification and understanding of some of the amples of cooperation between oncogenes and other gene prod functions of a group of cancer-causing genes, the oncogenes. ucts which modify the mode of action of the former. If we are The major path to the oncogenes came from the study of cancer- on the right track, then general principles may well emerge. causing viruses. The oncogenes have been recognized and stud Tumor formation in animals or transformation in cell culture ied by two separate but related groups of virologists focusing has been demonstrated with many different DNA-containing upon either the DNA (1) or RNA (2) tumor viruses (they even viruses (1). In most cases it has been possible to identify one or have separate meetings now that these fields have grown so a few viral genes and their products that are responsible for large). From their studies it has become clear that the oncogenes transformation or, in some cases, tumorigenesis. A list of these of each virus type have very different origins.
    [Show full text]
  • Tätigkeitsbericht 2007/2008
    Tätigkeitsbericht 2007/2008 8 200 / 7 0 20 Tätigkeitsbericht Stiftung bürgerlichen Rechts Martinistraße 52 · 20251 Hamburg Tel.: +49 (0) 40 480 51-0 · Fax: +49 (0) 40 480 51-103 [email protected] · www.hpi-hamburg.de Impressum Verantwortlich Prof. Dr. Thomas Dobner für den Inhalt Dr. Heinrich Hohenberg Redaktion Dr. Angela Homfeld Dr. Nicole Nolting Grafik & Layout AlsterWerk MedienService GmbH Hamburg Druck Hartung Druck + Medien GmbH Hamburg Titelbild Neu gestaltete Fassade des Seuchenlaborgebäudes Tätigkeitsbericht 2007/2008 Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie an der Universität Hamburg Martinistraße 52 · 20251 Hamburg Postfach 201652 · 20206 Hamburg Telefon: +49-40/4 80 51-0 Telefax: +49-40/4 80 51-103 E-Mail: [email protected] Internet: www.hpi-hamburg.de Das Heinrich-Pette-Institut ist Mitglied der Leibniz-Gemeinschaft (WGL) Internet: www.wgl.de Inhaltsverzeichnis Allgemeiner Überblick Vorwort ................................................................................................... 1 Die Struktur des Heinrich-Pette-Instituts .............................................. 2 Modernisierung des HPI erfolgreich abgeschlossen ............................ 4 60 Jahre HPI .............................................................................................. 5 Offen für den Dialog .............................................................................. 6 Preisverleihungen und Ehrungen .......................................................... 8 Personelle Veränderungen in
    [Show full text]
  • Inhibition of HIV-1 by an Anti-Integrase Single-Chain Variable
    Gene Therapy (1999) 6, 660–666 1999 Stockton Press All rights reserved 0969-7128/99 $12.00 http://www.stockton-press.co.uk/gt Inhibition of HIV-1 by an anti-integrase single-chain variable fragment (SFv): delivery by SV40 provides durable protection against HIV-1 and does not require selection M BouHamdan1, L-X Duan1, RJ Pomerantz1 and DS Strayer1,2 1The Dorrance H Hamilton Laboratories, Center for Human Virology, Division of Infectious Diseases, Department of Medicine; and 2Department of Pathology, Anatomy and Cell Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA Human immunodeficiency virus type I (HIV-1) encodes the SFv-IN was confirmed by Western blotting and several proteins that are packaged into virus particles. Inte- immunofluorescence staining, which showed that Ͼ90% of grase (IN) is an essential retroviral enzyme, which has SupT1 T-lymphocytic cells treated with SV(Aw) expressed been a target for developing agents to inhibit virus repli- the SFv-IN protein without selection. When challenged, cation. In previous studies, we showed that intracellular HIV-1 replication, as measured by HIV-1 p24 antigen expression of single-chain variable antibody fragments expression and syncytium formation, was potently inhibited (SFvs) that bind IN, delivered via retroviral expression vec- in cells expressing SV40-delivered SFv-IN. Levels of inhi- tors, provided resistance to productive HIV-1 infection in bition of HIV-1 infection achieved using this approach were T-lymphocytic cells. In the current studies, we evaluated comparable to those achieved using murine leukemia virus simian-virus 40 (SV40) as a delivery vehicle for anti-IN (MLV) as a transduction vector, the major difference being therapy of HIV-1 infection.
    [Show full text]
  • A Polyoma Mutant That Encodessmall T Antigen but Not Middle T Antigen
    MOLECULAR AND CELLULAR BIOLOGY, Dec. 1984, p. 2774-2783 Vol. 4, No. 12 0270-7306/84/122774-10$02.00/0 Copyright © 1984, American Society for Microbiology A Polyoma Mutant That Encodes Small T Antigen But Not Middle T Antigen Demonstrates Uncoupling of Cell Surface and Cytoskeletal Changes Associated with Cell Transformation T. JAKE LIANG, GORDON G. CARMICHAEL,t AND THOMAS L. BENJAMIN* Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115 Received 2 July 1984/Accepted 31 August 1984 The hr-t gene of polyoma virus encodes both the small and middle T (tumor) antigens and exerts pleiotropic effects on cells. By mutating the 3' splice site for middle T mRNA, we have constructed a virus mutant, Py8O8A, which fails to express middle T but encodes normal small and large T proteins. The mutant failed to induce morphological transformation or growth in soft agar, but did stimulate postconfluent growth of normal cells. Cells infected by Py8O8A became fully agglutinable by lectins while retaining normal actin cable architecture and normal levels of extracellular fibronectin. These properties of Py8O8A demonstrated the separability of structural changes at the cell surface from those in the cytoskeleton and extracellular matrix, parameters which have heretofore been linked in the action of the hr-t and other viral oncogenes. The early region of polyoma encodes three proteins de- substitution of phenylalanine for tyrosine at position 315 in tected as tumor (T) antigens. These polypeptides of 100,000 middle T has been made and studied in two laboratories, daltons (100K; large T), 56K (middle T), and 22K (small T) with different results.
    [Show full text]
  • Inactivation of Fbxw7 Impairs Dsrna Sensing and Confers Resistance to PD-1 Blockade
    Published OnlineFirst May 5, 2020; DOI: 10.1158/2159-8290.CD-19-1416 RESEARCH ARTICLE Inactivation of Fbxw7 Impairs dsRNA Sensing and Confers Resistance to PD-1 Blockade Cécile Gstalder1,2, David Liu1,3, Diana Miao1, Bart Lutterbach1,2, Alexander L. DeVine1,2, Chenyu Lin4, Megha Shettigar1,2, Priya Pancholi1,2, Elizabeth I. Buchbinder1, Scott L. Carter5,6, Michael P. Manos1, Vanesa Rojas-Rudilla7, Ryan Brennick1, Evisa Gjini8, Pei-Hsuan Chen8, Ana Lako8, Scott Rodig8,9, Charles H. Yoon10, Gordon J. Freeman1, David A. Barbie1, F. Stephen Hodi1, Wayne Miles4, Eliezer M. Van Allen1, and Rizwan Haq1,2 Downloaded from cancerdiscovery.aacrjournals.org on September 26, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst May 5, 2020; DOI: 10.1158/2159-8290.CD-19-1416 ABSTRACT The molecular mechanisms leading to resistance to PD-1 blockade are largely unknown. Here, we characterize tumor biopsies from a patient with melanoma who displayed heterogeneous responses to anti–PD-1 therapy. We observe that a resistant tumor exhibited a loss-of-function mutation in the tumor suppressor gene FBXW7, whereas a sensitive tumor from the same patient did not. Consistent with a functional role in immunotherapy response, inactivation of Fbxw7 in murine tumor cell lines caused resistance to anti–PD-1 in immunocompetent animals. Loss of Fbxw7 was associated with altered immune microenvironment, decreased tumor-intrinsic expression of the double-stranded RNA (dsRNA) sensors MDA5 and RIG1, and diminished induction of type I IFN and MHC-I expression. In contrast, restoration of dsRNA sensing in Fbxw7-deficient cells was suffi- cient to sensitize them to anti–PD-1.
    [Show full text]
  • Accumulation of Dephosphorylated 4EBP After Mtor Inhibition with Rapamycin Is Sufficient to Disrupt Paracrine Transformation By
    Oncogene (2014) 33, 2405–2412 & 2014 Macmillan Publishers Limited All rights reserved 0950-9232/14 www.nature.com/onc SHORT COMMUNICATION Accumulation of dephosphorylated 4EBP after mTOR inhibition with rapamycin is sufficient to disrupt paracrine transformation by the KSHV vGPCR oncogene D Martin, Q Nguyen, A Molinolo and JS Gutkind Dysregulation of the PI3K/Akt/mTOR pathway is one of the most frequent events in human cancer. However, the clinical benefits of PI3K/Akt/mTOR inhibitors have not yet achieved their predicted potential in many of the most prevalent human cancers. Of interest, treatment of Kaposi’s sarcoma (KS) patients with rapamycin provided the first evidence of the antineoplastic activity of mTOR inhibitors in humans, becoming the standard of care for KS arising in renal transplant patients. Thus, the study of KS may provide a unique opportunity to dissect the contribution of specific mTOR downstream targets to cancer development. The KS- associated herpesvirus (KSHV) is the etiological agent for KS, and the KSHV-encoded oncogene viral-G protein-coupled receptor (vGPCR) promotes the potent activation of the PI3K-Akt-mTOR pathway by both direct and paracrine mechanisms. We focused on a direct target of mTOR, EIF4EBP1/2/3 (4EBP), which inhibits the translation of eukaryotic initiation factor 4E (eiF4E)-bound mRNAs. 4EBP phosphorylation by mTOR relieves its inhibitory activity, hence resulting in increased eiF4E-dependent mRNA translation. We developed a paracrine transformation model, recapitulating the cellular composition of KS lesions, in which vGPCR-expressing cells promote the rapid proliferation of endothelial cells, thus expressing KSHV-latent genes by the release of growth factors.
    [Show full text]
  • Mutational Landscape Differences Between Young-Onset and Older-Onset Breast Cancer Patients Nicole E
    Mealey et al. BMC Cancer (2020) 20:212 https://doi.org/10.1186/s12885-020-6684-z RESEARCH ARTICLE Open Access Mutational landscape differences between young-onset and older-onset breast cancer patients Nicole E. Mealey1 , Dylan E. O’Sullivan2 , Joy Pader3 , Yibing Ruan3 , Edwin Wang4 , May Lynn Quan1,5,6 and Darren R. Brenner1,3,5* Abstract Background: The incidence of breast cancer among young women (aged ≤40 years) has increased in North America and Europe. Fewer than 10% of cases among young women are attributable to inherited BRCA1 or BRCA2 mutations, suggesting an important role for somatic mutations. This study investigated genomic differences between young- and older-onset breast tumours. Methods: In this study we characterized the mutational landscape of 89 young-onset breast tumours (≤40 years) and examined differences with 949 older-onset tumours (> 40 years) using data from The Cancer Genome Atlas. We examined mutated genes, mutational load, and types of mutations. We used complementary R packages “deconstructSigs” and “SomaticSignatures” to extract mutational signatures. A recursively partitioned mixture model was used to identify whether combinations of mutational signatures were related to age of onset. Results: Older patients had a higher proportion of mutations in PIK3CA, CDH1, and MAP3K1 genes, while young- onset patients had a higher proportion of mutations in GATA3 and CTNNB1. Mutational load was lower for young- onset tumours, and a higher proportion of these mutations were C > A mutations, but a lower proportion were C > T mutations compared to older-onset tumours. The most common mutational signatures identified in both age groups were signatures 1 and 3 from the COSMIC database.
    [Show full text]
  • Adaptive Capabilities of the Pi3k/Akt/Mtor Pathway in Acute Myeloid Leukemia Revealed by the Use of Selective Inhibitors
    Alma Mater Studiorum – Università di Bologna SCIENZE BIOMEDICHE: PROGETTO 5 “SCIENZE MORFOLOGICHE UMANE E MOLECOLARI” Ciclo XXV SSD : BIO 16, SETTORE CONCORSUALE :05H1 ADAPTIVE CAPABILITIES OF THE PI3K/AKT/MTOR PATHWAY IN ACUTE MYELOID LEUKEMIA REVEALED BY THE USE OF SELECTIVE INHIBITORS Presentata da Jessika Bertacchini Relatori Prof.ssa Lucia Manzoli Prof.ssa Sandra Marmiroli Coordinatore Chiar. mo Prof. Lucio Cocco TABLE OF CONTENTS o ABSTRACT o INTRODUCTION o ACUTE MYELOID LEUKEMIA o PROGNOSIS AND GENETICS o DEREGULATED SIGNAL TRANSDUCTION PATHWAYS IN ACUTE MYELOID LEUKEMIA o PI3K/AKT/MTOR SIGNAL TRANSDUCTION PATHWAY IN ACUTE MYELOID LEUKEMIA o PI3K o AKT/PKB o Mtor o NEGATIVE REGULATION OF PI3K/AKT/mTOR PATHWAY o PI3K/AKT/mTOR PATHWAY AND SURVIVAL o PI3K/AKT/mTOR PATHWAY AND CELL CYCLE o PI3K/AKT/mTOR PATHWAY AND METABOLISM o PI3K/AKT/mTOR INHIBITORS o PI3K INHIBITORS o AKT INHIBITORS o mTOR INHIBITORS o TYROSINE KINASE RECEPTOR o TYROSINE KINASE RECEPTOR IN ACUTE MYELOID LEUKEMIA o AIMS o MATERIALS AND METHODS o PATIENTS DEMOGRAPHICS o CELL CULTURE AND DRUG TREATMENTS o ARRAY ASSEMBLY o RESULTS o RESULTS o DISCUSSION o BIBLIOGRA 1.ABSTRACT The objective of the study was to investigate the sensitivity of primary blasts from AML patients to PI3K/Akt/mTor inhibitors through reverse-phase protein microarray. Reverse-phase microarray assays using phosphospecific antibodies (RPPA) can directly measure levels of phosphorylated protein isoforms. Mapping of deregulated kinases and protein signaling networks within tumors can provide a means to stratify patients with shared biological characteristics to the most optimal treatment, and identify drug targets. In particular, the PI3K/AKT/mTOR signaling pathways are frequently activated in blast cells from patients with acute myelogenous leukemia (AML), a neoplastic disorder characterized by the accumulation of genetically altered myelogenous cells displaying deregulated intracellular signalling pathways and aggressive clinical behavior with poor prognosis.
    [Show full text]
  • Review Article Human Polyomaviruses in Skin Diseases
    SAGE-Hindawi Access to Research Pathology Research International Volume 2011, Article ID 123491, 12 pages doi:10.4061/2011/123491 Review Article Human Polyomaviruses in Skin Diseases Ugo Moens,1 Maria Ludvigsen,1 and Marijke Van Ghelue2 1 Institute of Medical Biology, Faculty of Health Sciences, University of Tromsø, 9037 Tromsø, Norway 2 Department of Medical Genetics, University Hospital of Northern-Norway, 9038 Tromsø, Norway Correspondence should be addressed to Ugo Moens, [email protected] Received 28 February 2011; Accepted 29 June 2011 Academic Editor: Gerardo Ferrara Copyright © 2011 Ugo Moens et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Polyomaviruses are a family of small, nonenveloped viruses with a circular double-stranded DNA genome of ∼5,000 base pairs protected by an icosahedral protein structure. So far, members of this family have been identified in birds and mammals. Until 2006, BK virus (BKV), JC virus (JCV), and simian virus 40 (SV40) were the only polyomaviruses known to circulate in the human population. Their occurrence in individuals was mainly confirmed by PCR and the presence of virus-specific antibodies. Using the same methods, lymphotropic polyomavirus, originally isolated in monkeys, was recently shown to be present in healthy individuals although with much lower incidence than BKV, JCV, and SV40. The use of advanced high-throughput sequencing and improved rolling circle amplification techniques have identified the novel human polyomaviruses KI, WU, Merkel cell polyomavirus, HPyV6, HPyV7, trichodysplasia spinulosa-associated polyomavirus, and HPyV9.
    [Show full text]