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Prepublished online as a Blood First Edition Paper on July 25, 2002; DOI 10.1182/blood-2001-12-0372. This Article Full Text (PDF) All Versions of this Article: 2001-12-0372v1 100/12/4129    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Arnulf, B. Articles by Hermine, O. Search for Related Content PubMed PubMed Citation Articles by Arnulf, B. Articles by Hermine, O. Social Bookmarking                   What's this? Submitted January 7, 2002 Accepted July 2, 2002 Human T cell lymphotropic virus oncoprotein tax represses TGF-ß1 signaling in human T cells via c-Jun activation: a potential mechanism of HTLV-I leukemogenesis Bertrand Arnulf, Aude Villemain, Christophe Nicot, Elodie Mordelet, Pierre Charneau, Joelle Kersual, Yael Zermati, Alain Mauviel, Ali Bazarbachi, and Olivier Hermine* Hematology and CNRS UMR 8603 and University Rene Descartes PARIS V, Hopital Necker, Paris, France Basic Research Laboratory, Natiomal Cancer Institute, Bethesda, MD, USA Unite d'Oncologie Virale, Institut Pasteur, Paris, France INSERM Unite 532, Hopital St Louis, Paris, France Internal Medicine, American University of Beirut, Beirut, Lebanon * Corresponding author; email: hermine{at}necker.fr. Human T cell leukemia virus I is the etiological agent of adult T cell leukemia (ATL), an aggressive T cell malignancy. The viral oncoprotein Tax, through the activation of NF-B, CREB and AP-1 pathways, is a transcriptional regulator of critical genes for T cell homeostasis. In ATL cells, activated AP-1 complexes induce the production of TGF-ß1. TGF-ß1 is an inhibitor of T cell proliferation and cytotoxicity. Here we show that, in contrast to normal peripheral T cells, ATL cells are resistant to TGF-ß1 induced growth inhibition. The retroviral transduction of the Tax protein in peripheral T cells resulted in the loss of TGF-ß1 sensitivity. Transient transfection of Tax in HepG2 cells specifically inhibited Smad/TGF-ß1 signaling in a dose dependent manner. In the presence of Tax transfection, increasing amounts of Smad3 restored TGF-ß1 signaling. Tax mutants unable to activate NF-B or CREB pathways were also able to repress Smad3 transcriptional activity. Next we have demonstrated that Tax inhibits TGF-ß1 signaling by reducing the Smad3 DNA binding activity. However, Tax did not decrease the expression and the nuclear translocation of Smad3 nor did it interact physically with Smad3. Rather, Tax induced c-Jun N-terminal kinase (JNK) activity and c-Jun phosphorylation leading to the formation of Smad3/c-Jun complexes. Whereas c-Jun alone abrogates Smad3 DNA binding, cotransfection of Tax and of a dominant negative form of JNK or a c-Jun antisense restored Smad3 DNA binding activity and TGF-ß1 responsiveness. In ATL and in normal T cells transduced by Tax, c-Jun was constitutively phosphorylated. Thus, we describe a new function of Tax, as a repressor of TGF-ß1 signaling through JNK/c-Jun constitutive activation, which may play a critical role in ATL leukemogenesis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: T. Hidaka, S. Nakahata, K. Hatakeyama, M. Hamasaki, K. Yamashita, T. Kohno, Y. Arai, T. Taki, K. Nishida, A. Okayama, et al. 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