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Centro de Biología Molecular "Severo Ochoa" Consejo Superior de Investigaciones Cientificas-Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain
Dysregulation of cytokine secretion plays an important role in AIDS
pathogenesis. Here, we demonstrate that expression of HIV-1 Tat protein
in Jurkat cells induces a severe impairment of IL-2 but not TNF gene
transcription. Interestingly, this inhibition correlates with the
effect of the viral protein on the transactivation of the CD28RE/AP1
composite element (-164/-154), but not with that observed on the
NFAT/AP1 site of the IL-2 gene promoter, neither with the effect on
NF-
B- nor AP1-independent binding sites. Endogenous expression of
Tat induced a decrease in the amount of the specific protein complex
bound to the CD28RE/AP1 probe after PMA plus calcium ionophore
stimulation. This effect was accompanied by qualitative alterations of
the AP1 complex. Thus, in wild-type Jurkat cells, c-jun was absent from
the complex, whereas in Tat-expressing cells, c-jun was increasingly
recruited overtime. By contrast, similar amounts of
c-rel and a small amount of NFAT1 were detected
both in wild type and in Jurkat Tat+ cells. Furthermore,
Tat not only induced the participation of c-jun in the cooperative
complex but also a decrease in its transactivation activity alone or in
combination with c-rel. Thus, the interaction of Tat
with the components of this rel/AP1 cooperative complex seems to induce
quantitative and qualitative alterations of this complex as activation
progresses, resulting in a decrease of IL-2 gene transcription.
Altogether our results suggest the existence of tuned mechanisms that
allow the viral protein to specifically affect cooperative interactions
between transcription factors.
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