title: HBZ-mediated shift of JunD from growth suppressor to tumor promoter in leukemic cells by inhibition of ribosomal protein S25 expression.
abstract: Human T-cell leukemia virus type 1 (HTLV-1) basic-leucine zipper (bZIP) factor (HBZ) is a key player in proliferation and transformation of HTLV-1-infected cells, thus contributing to adult T-cell leukemia (ATL) development. HBZ deregulates gene expression within the host cell by interacting with several cellular partners. Through its C-terminal ZIP domain, HBZ is able to contact and activate JunD, a transcription factor of the AP-1 family. JunD mRNA is intronless but can generate two protein isoforms by alternative translation initiation: JunD full-length and Δ JunD, an N-terminal truncated form unresponsive to the tumor suppressor menin. Using various cell lines and primary T-lymphocytes, we show that after serum deprivation HBZ induces the expression of Δ JunD isoform. We demonstrate that, unlike JunD, Δ JunD induces proliferation and transformation of cells. To decipher the mechanisms for Δ JunD production, we looked into the translational machinery and observed that HBZ induces nuclear retention of RPS25 mRNA and loss of RPS25 protein expression, a component of the small ribosomal subunit. Therefore, HBZ bypasses translational control of JunD uORF and favors the expression of Δ JunD. In conclusion, we provide strong evidences that HBZ induces Δ JunD expression through alteration of the cellular translational machinery and that the truncated isoform Δ JunD has a central role in the oncogenic process leading to ATL.
authors.affiliation: IRIM (ex-CPBS)-UMR 9004, Research Institute in Infectiology of Montpellier, University of Montpellier, CNRS, Montpellier, France.
authors.forename: M
authors.initials: M
authors.lastname: Terol
authors.affiliation: IRIM (ex-CPBS)-UMR 9004, Research Institute in Infectiology of Montpellier, University of Montpellier, CNRS, Montpellier, France.|Belgium Molecular and Cellular Epigenetics, Interdisciplinary Cluster for Applied Genoproteomics (GIGA) of University of Liège (ULg), Liège, Belgium.
authors.forename: H
authors.initials: H
authors.lastname: Gazon
authors.affiliation: Brody School of Medicine, Department of Microbiology and Immunology, East Carolina University, Greenville, NC, USA.
authors.forename: I
authors.initials: I
authors.lastname: Lemasson
authors.affiliation: Laboratoire de Biologie et Modélisation de la Cellule, CNRS - UCBL UMR 5239, INSERM U 1210 UMS 3444 SFR Biosciences Lyon-Gerland, Ecole Normale Supérieure de Lyon, Lyon, France.
authors.forename: M
authors.initials: M
authors.lastname: Duc-Dodon
authors.affiliation: Université du Québec à Montréal, Département des sciences biologiques, and Centre de recherche BioMed, Montréal, QC, Canada.
authors.forename: B
authors.initials: B
authors.lastname: Barbeau
authors.affiliation: Laboratoire de Virologie-Immunologie JE2503, Centre Hospitalier et Universitaire de Martinique, Fort de France Martinique, Martinique, France.
authors.forename: R
authors.initials: R
authors.lastname: Césaire
authors.affiliation: IRIM (ex-CPBS)-UMR 9004, Research Institute in Infectiology of Montpellier, University of Montpellier, CNRS, Montpellier, France.
authors.forename: J-M
authors.initials: JM
authors.lastname: Mesnard
authors.affiliation: IRIM (ex-CPBS)-UMR 9004, Research Institute in Infectiology of Montpellier, University of Montpellier, CNRS, Montpellier, France.
authors.forename: J-M
authors.identifier: 0000-0002-9677-9703
authors.initials: JM
authors.lastname: Péloponèse
mesh_terms: D050976:Basic-Leucine Zipper Transcription Factors / Q000502:physiology*; D001692:Biological Transport; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002472:Cell Transformation, Viral / Q000235:genetics*; D016895:Culture Media, Serum-Free; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics*; D015967:Gene Expression Regulation, Viral / Q000235:genetics*; D057809:HEK293 Cells; D015490:HTLV-I Infections / Q000097:blood; D006801:Humans; D014176:Protein Biosynthesis / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D012191:Retroviridae Proteins / Q000502:physiology*; D012269:Ribosomal Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D012270:Ribosomes / Q000378:metabolism; D013601:T-Lymphocytes / Q000473:pathology / Q000821:virology; D014162:Transfection
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D016895:Culture Media, Serum-Free; C479751:HBZ protein, human T-cell leukemia virus type I; C559371:JunD protein, human; C105373:MEN1 protein, human; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; C489168:RPS25 protein, human; D012191:Retroviridae Proteins; D012269:Ribosomal Proteins