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Prepublished online as a Blood First Edition Paper on July 25, 2002; DOI 10.1182/blood-2001-12-0372.
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Blood, 1 December 2002, Vol. 100, No. 12, pp. 4129-4138
NEOPLASIA
Human T-cell lymphotropic virus oncoprotein Tax represses
TGF- 1 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,
Joëlle Kersual,
Yaël Zermati,
Alain Mauviel,
Ali Bazarbachi, and
Olivier Hermine
From the Centre National de la Recherche Scientifique
Unité Mixte de Recherche (CNRS UMR) 8603, Hopital Necker
Université Paris V, the Unité d'oncologie virale, Institut
Pasteur, and the INSERM U532, Institut de recherche sur la peau,
Hopital Saint Louis, Paris, France; the Division of Basic
Sciences, Basic Research Laboratory, National Cancer Institute,
Bethesda, MD; and the Department of Internal Medicine, American
University of Beirut, Beirut, Lebanon.
Human T-cell leukemia virus I is the etiologic agent of adult
T-cell leukemia (ATL), an aggressive T-cell malignancy. The viral
oncoprotein Tax, through the activation of nuclear factor B (NF-B), CCAAT-enhancer binding protein (CREB), and activated protein-1 (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 transforming growth factor  1
(TGF-1). TGF-1 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-1-induced growth inhibition.
The retroviral transduction of the Tax protein in peripheral T cells
resulted in the loss of TGF-1 sensitivity. Transient transfection of
Tax in HepG2 cells specifically inhibited Smad/TGF-1 signaling in a
dose-dependent manner. In the presence of Tax transfection, increasing
amounts of Smad3 restored TGF-1 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-1 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-1 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-1 signaling
through JNK/c-Jun constitutive activation, which may play a critical
role in ATL leukemogenesis.
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