Vav‐induced activation of the human IFN‐γ gene promoter is mediated by upregulation of AP‐1 activity

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Abstract
The role of Vav in the transcriptional regulation of the human interferon‐γ (IFN‐γ) promoter was investigated. Overexpression of Vav in Jurkat‐TAg cells enhanced T cell receptor (TCR)‐induced activation of a luciferase (Luc) reporter gene construct driven by cis‐regulatory element of the IFN‐γ gene (−346 to +7). Electrophoresis mobility shift and Luc reporter assays demonstrated that the DNA‐binding and transcriptional activity of the proximal AP‐1‐dependent NFAT site (positions −172 to −138), the AP‐1/Ying‐Yang 1 (YY1)‐binding site (−209 to −184), and a consensus AP‐1‐binding site were upregulated by Vav. Vav enhanced TCR‐induced activation of c‐Jun N‐terminal kinase (JNK) and its upstream regulator, Rho family GTPases. Finally, coexpression of a dominant‐negative Rac1 mutant suppressed Vav‐mediated upregulation of the transcriptional and DNA‐binding activity of the proximal NFAT/AP‐1 site and the AP‐1/YY1 site, as well as the complete IFN‐γ promoter activity. Vav activates the IFN‐γ promoter via upregulation of AP‐1‐binding through a Rac1/JNK pathway.