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J. Biol. Chem., Vol. 277, Issue 49, 47136-47148, December 6, 2002

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Identification of Three NFAT Binding Motifs in the 5'-Upstream Region of the Human CD3 Gene That Differentially Bind NFATc1, NFATc2, and NF-B p50^*

Bassam M. Badran, Steven M. Wolinsky^§, Arsène Burny, and Karen E. Willard-Gallo^¶

From the  Laboratory of Experimental Hematology, Faculty of Medicine, University of Brussels, 121 Blvd. de Waterloo, Brussels B1000, Belgium and the ^§ Division of Infectious Diseases, Department of Medicine, Northwestern University Medical School, Chicago, Illinois 60611

Human immunodeficiency virus, type 1 (HIV-1) infection of CD4⁺ T cells progressively abrogates T cell receptor (TCR)·CD3 function and surface expression by specifically interfering with CD3 gene transcription. Our data show that the loss of CD3 transcripts begins very early after infection and accumulates to a >90% deficiency before a significant effect on surface receptor density is apparent. Blocking TCR·CD3-directed NFAT activation with cyclosporin A provokes a partial re-expression of CD3 gene transcripts and surface complexes in a time- and dose-dependent manner. We have identified three NFAT consensus sequences (5'-GGAAA-3') in the 5'-upstream region of the human CD3 gene at: 124 to 120 (NFAT₁), 384 to 380 (NFAT₂), and +450 to +454 (NFAT₃) from the first transcription initiation site. Using electrophoretic mobility shift and supershift assays, we show that NFATc2 alone binds to the NFAT₂ motif; however, complexes containing either NFATc2 or NFATc1 plus NF-B p50 bind to the NFAT₁ and NFAT₃ sites. We further demonstrate that NFATc1 and NF-B p50 bind in the same protein·DNA complex and that a fourth Ala added to the core sequence (5'-GGAAAA-3') in NFAT₁, and NFAT₃ is critical for their binding. Finally, we have shown that an increase in the binding of nuclear NFATc2, NFATc1, and NF-B p50 to these three motifs is correlated with a progressive loss of CD3 transcripts after HIV-1 infection.

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