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The HTLV-I Tax oncoprotein targets the retinoblastoma protein for proteasomal degradation

Oncogene volume 24, pages 525–540 (2005)Cite this article

Abstract

Human T-cell leukemia virus type-I (HTLV-I), the etiologic agent of adult T-cell leukemia (ATL), is estimated to affect 10–20 million people worldwide. The transforming ability of HTLV-I has been largely attributed to the viral protein Tax, which modulates the activity of several well-known cell cycle regulators. An important cell cycle regulator, the retinoblastoma (Rb) protein, is often inactivated in many cancers including virally induced cancers. Upon examination of Rb status, we observed a decrease in Rb protein expression in HTLV-1-infected cell lines as well as in ex vivo ATL patient samples. Transient transfection assays indicated that decreased Rb protein levels were Tax dependent. Here, we demonstrate for the first time that Tax directly associates with Rb. This interaction was localized within the B pocket of Rb and the C-terminus of Tax (aa 245–353). Within the C-terminus of Tax, we have identified an LXCXE-like motif, that when mutated resulted in the loss of Tax/Rb interaction. Furthermore, through the use of proteasome inhibitors, such as MG-132, in vivo and proteasome degradation assays in vitro, we found that Tax destabilizes the hypo-phosphorylated (active) form of Rb via the proteasome pathway. Therefore, we propose a model whereby Tax targets Rb to the proteasome by acting as a molecular bridge bringing Rb into contact with the proteasome for degradation.

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Acknowledgements

We acknowledge the Kashanchi lab members for their constructive criticism and helpful discussions. We thank Dr Scott Gitlin (University of Michigan, Ann Arbor, MI, USA) for the Tax polyclonal antibody, Dr Sibylle Mittnacht (Chester Beatty Laboratories, London, UK) for the GST-Rb constructs, Dr William Sellers (Harvard Medical School, Boston, MA, USA) for the HA-Rb construct, and Dr Warner Greene (Gladstone Institute of Virology and Immunology, CA, USA) for the pBC12-Tax M44 and -M41 constructs. We also thank Dr Chen Zeng (Department of Physics, The George Washington University) for his assistance in molecular modeling of Rb and Tax proteins (data not shown). K Kehn was supported by a predoctoral research fellowship from the DOD Breast Cancer Research Program (DAMD17-03-1-0198). C de la Fuente was supported by NIH Grant;AI061560. R Mahieux received financial support from Association pour la Recherche sur le Cancer. This work was supported in part by NIH Grants AI44357, AI43894, and AI061560 to F Kashanchi and partially by a Research Enhancement Fund (REF) from The George Washington University to F Kashanchi and A Vertes.

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  1. Kylene Kehn and Cynthia de la Fuente: These two authors contributed equally to this work

  2. Maria Elena Bottazzi and Fatah Kashanchi: These two share senior authorship

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, The George Washington University School of Medicine, Washington, DC, 20037, USA

    Kylene Kehn, Cynthia de la Fuente, Katharine Strouss, Reem Berro, Anne Pumfery & Fatah Kashanchi

  2. Virus Tumor Biology Section, Basic Research Laboratory, National Cancer Institute, National Institutes of Health, Building 41/B201, 9000 Rockville Pike, Bethesda, MD, 20892, USA

    Hua Jiang & John Brady

  3. Unite d'Epidemiologie et Physiopathologie des Virus Oncogenes, Departement du SIDA et des Retrovirus, Institut Pasteur, 75724, Paris Cedex, 15, France

    Renaud Mahieux

  4. Department of Microbiology and Tropical Medicine, The George Washington University Medical Center, Washington, DC, 20037, USA

    Maria Elena Bottazzi

  5. The Institute for Genomic Research (TIGR), Rockville, MD, 20850, USA

    Fatah Kashanchi

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Kehn, K., Fuente, C., Strouss, K. et al. The HTLV-I Tax oncoprotein targets the retinoblastoma protein for proteasomal degradation. Oncogene 24, 525–540 (2005). https://doi.org/10.1038/sj.onc.1208105

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