Extracellular Tat activates c-fos promoter in low serum-starved CD4+ T cells.
The regulatory human immunodeficiency virus-1 (HIV-1) Tat protein shows pleiotropic effects on the survival and growth of both HIV-1-infected and uninfected CD4+ T lymphocytes. In this study, we have demonstrated that low concentrations (10 ng/ml) of extracellular Tat protein induce the expression of both c-fos mRNA and protein in serum-starved Jurkat CD4+ lymphoblastoid T cells. Using deletion mutants, we demonstrates that the SRE, CRE and, to a lesser extent, also the SIE domains (all placed in the first 356 bp of c-fos promoter) play a key role in mediating the response to extracellular Tat. Moreover, the ability of Tat to activate the transcriptional activity of c-fos promoter was consistently decreased by pretreatment with the ERK/MAPK kinase inhibitor PD98058. Activation of c-fos is functional as demonstrated by induction of the AP-1 transcription factor, which is involved in the regulation of critical genes for the activation of T lymphocytes, such as interleukin 2. The Tat-mediated induction of c-fos and AP-1 in uninfected lymphoid T cells may contribute to explain the immune hyperactivation that characterizes the progression to autoimmuno deficiency syndrome and constitutes the optimal environment for HIV-1 replication, occurring predominantly in activated/proliferating CD4+ T cells.
Gibellini
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Department of Clinical and Experimental Medicine, Microbiology Section, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy. rabbiloew@hotmail.com
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Ponti
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Celeghini
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Melloni
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La Placa
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Zauli
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D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D015696:Gene Products, tat / Q000494:pharmacology*; D016762:Genes, fos; D006801:Humans; D019169:Jurkat Cells; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism
D004791:Enzyme Inhibitors; D005419:Flavonoids; D015696:Gene Products, tat; D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1; D020929:Mitogen-Activated Protein Kinase Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one