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Transcriptional control and signal transduction, cell cycle

HBZ-mediated shift of JunD from growth suppressor to tumor promoter in leukemic cells by inhibition of ribosomal protein S25 expression

Leukemia volume 31, pages 2235–2243 (2017)Cite this article

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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.

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Acknowledgements

We kindly thank Dr Mauro for the gift of p3(AUG)− vectors, Dr Benkirane for the gift of pOZ vectors. We would like to thank Dr Polakowski for readings of manuscript. This work was supported by the ARC foundation, the Fondation pour la Recherche Médicale (Equipe FRM DEQ20161136701), the GEFLUC Languedoc-Roussillon and the Ligue Contre le Cancer, Comité Hérault. HG was supported by a grant from the Conseil Régional de la Martinique.

Author contributions

J-MP designed and performed research. MT and HG performed research and equally contributed to the paper. DD, BB and RC contributed vital new reagents or analytical tools; J-MM and J-MP wrote the manuscript.

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Authors and Affiliations

  1. IRIM (ex-CPBS)-UMR 9004, Research Institute in Infectiology of Montpellier, University of Montpellier, CNRS, Montpellier, France

    M Terol, H Gazon, J-M Mesnard & J-M Péloponèse Jr

  2. Belgium Molecular and Cellular Epigenetics, Interdisciplinary Cluster for Applied Genoproteomics (GIGA) of University of Liège (ULg), Liège, Belgium

    H Gazon

  3. Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA

    I Lemasson

  4. 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

    M Duc-Dodon

  5. Département des sciences biologiques, Université du Québec à Montréal, and Centre de recherche BioMed, Montréal, QC, Canada

    B Barbeau

  6. Laboratoire de Virologie-Immunologie JE2503, Centre Hospitalier et Universitaire de Martinique, Fort de France Martinique, Martinique, France

    R Césaire

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  1. M Terol
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  3. I Lemasson
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  4. M Duc-Dodon
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Correspondence to J-M Mesnard or J-M Péloponèse Jr.

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Terol, M., Gazon, H., Lemasson, I. et al. HBZ-mediated shift of JunD from growth suppressor to tumor promoter in leukemic cells by inhibition of ribosomal protein S25 expression. Leukemia 31, 2235–2243 (2017). https://doi.org/10.1038/leu.2017.74

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