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J Biol Chem, Vol. 275, Issue 14, 10551-10560, April 7, 2000
From The human T cell leukemia/lymphotropic virus type
1 (HTLV-1) Tax protein strongly activates viral and cellular gene
transcription. It mainly functions by interacting with cellular
transcription factors and the KIX domain of the p300/CBP coactivators.
Tax can also repress the transcription of cellular genes through the
basic helix-loop-helix (bHLH) protein family. To investigate the
molecular mechanisms of this Tax-mediated inhibition, we analyzed its
effect on the transcriptional activity of the myogenic MyoD protein, which was used as a paradigm of bHLH factors. In this study, we show
that overexpression of the p300 coactivator in transient transfection
assays was sufficient to rescue MyoD repression by Tax. Furthermore, an
N-terminal domain of p300 (amino acids 379-654) containing the region
of KIX serving as the Tax binding site was found, when overexpressed,
to potentiate Tax-mediated transactivation of HTLV-1 proviral as well
as MyoD-dependent transcription, and to antagonize the
inhibition by Tax of the transcriptional activity of MyoD. These
results revealing the presence of an N-terminal MyoD binding site were
confirmed by in vitro protein-protein interaction assays
that demonstrate that MyoD binds to the KIX domain of p300 and that Tax
competes with MyoD binding in a nonreciprocal manner. These
observations provide evidence that Tax binding to the KIX domain of
p300 prevents bHLH proteins from contacting this N-terminal domain of
the coactivator, thus resulting in their transcriptional repression. As
bHLH proteins are implicated in many developmental fate decisions,
especially during thymopoiesis, Tax-mediated inhibition of their
transcriptional activity may contribute to the induction of
HTLV-1-linked leukemogenesis.
The Human T Cell Leukemia/Lymphotropic Virus Type 1 Tax Protein
Represses MyoD-dependent Transcription by Inhibiting
MyoD-binding to the KIX Domain of p300
A POTENTIAL MECHANISM FOR Tax-MEDIATED REPRESSION OF THE
TRANSCRIPTIONAL ACTIVITY OF BASIC HELIX-LOOP-HELIX FACTORS*
§,
Immuno-Virologie Moléculaire et
Cellulaire, Unité Mixte de Recherche 5537, CNRS-Université
Claude Bernard Lyon I, Faculté de Médecine Lyon Laennec,
69372 Lyon Cedex 8, France and the ¶ Institut de Recherches
Microbiologiques J.-M. Wiame, B-1070 Brussels, Belgium
*
This work was supported in part by institutional grants from
CNRS and the French Ministère de l'Enseignement Supérieur
et de la Recherche and by a grant from Agence Nationale de Recherches sur le SIDA.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Immuno-Virologie
Moléculaire et Cellulaire, UMR 5537, Faculté de
Médecine Lyon-Laennec, Rue Guillaume Paradin, 69372 Lyon
Cedex 08, France. Tel.: 33-0-4-78-77-86-17; Fax: 33-0-4-78-77-87-31;
E-mail: gazzolo@laennec.univ-lyon1.fr.
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