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J. Biol. Chem., Vol. 275, Issue 40, 30925-30933, October 6, 2000

This Article Full Text Full Text (PDF) All Versions of this Article: 275/40/30925    most recent M005535200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Li, X. Articles by Marasco, W. A. Search for Related Content PubMed PubMed Citation Articles by Li, X. Articles by Marasco, W. A. Social Bookmarking                      What's this?

Grb3-3 Is Up-regulated in HIV-1-infected T-cells and Can Potentiate Cell Activation through NFATc^*

Xuguang Li^§, Marie-Christine Multon^¶, Yvette Henin^¶, Fabien Schweighoffer, Corinne Venot^¶, Juliana Josef, Changhong Zhou, Joyce LaVecchio, Patricia Stuckert, Monika Raab, Abner Mhashilkar, Bruno Tocqué, and Wayne A. Marasco^**

From the Departments of  Cancer Immunology and AIDS and ^** Medicine, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, ^¶ Aventis Pharma, Inc., 13 quai Jules Guesde, BP14, 94403 Vitry-sur-Seine Cedex, France, and  Exonhit Therapeutics, 75013 Paris, France

The MAPK pathway is required for T-cell activation; however, its role in modulating T-cell function following human immunodeficiency virus type 1 (HIV-1) infection is poorly understood. In this report, we investigated whether Grb3-3, an isoform of the Grb2 (growth factor receptor-bound protein-2) adaptor molecule that is associated with the MAPK pathway, could be involved. We found that Grb3-3, but not its isoform Grb2, is markedly up-regulated in CD4⁺ peripheral blood mononuclear cells derived from either in vitro HIV-1-infected cultures or HIV-1-infected human subjects. Analysis of HIV-1 gene products indicated that Tat and Nef, both of which have been implicated in modulating T-cell function, can independently induce expression of Grb3-3. By using NFAT/AP-1, AP-1, or NFAT reporter assays, we found that Grb3-3 can potentiate NFAT (but not AP-1) promoter activity in Jurkat T-cells upon engagement of the T-cell receptor and CD28 co-receptor. In addition, potentiation of NFAT by Grb3-3 is substantially suppressed by MEKK1, a kinase that may play an important role in retaining NFAT in the cytoplasm, and by cyclosporin A. Finally, we also found that Grb3-3 potentiates HIV-1 long terminal (LTR) repeat promoter activity following T-cell receptor stimulation, an effect that can be largely suppressed by cyclosporin A. Taken together, this study indicates that Grb3-3 is a cellular factor that can be up-regulated by HIV-1. In addition, Grb3-3 can also function as a positive factor for T-cell activation and, in doing so, may aid in establishing an intracellular environment that can optimally support HIV-1 replication.

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