Vav-induced activation of the human IFN-gamma gene promoter is mediated by upregulation of AP-1 activity.
The role of Vav in the transcriptional regulation of the human interferon-gamma (IFN-gamma) 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-gamma 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-gamma promoter activity. Vav activates the IFN-gamma promoter via upregulation of AP-1-binding through a Rac1/JNK pathway.
Kaminuma
Osamu
O
Department of Immunology, The Tokyo Metropolitan Institute of Medical Science, 2-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8613, Japan.
Elly
Chris
C
Tanaka
Yoshihiko
Y
Mori
Akio
A
Liu
Yun-Cai
YC
Altman
Amnon
A
Miyatake
Shoichiro
S
D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics*; D048031:JNK Mitogen-Activated Protein Kinases; D019169:Jurkat Cells / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology*; D051567:Proto-Oncogene Proteins c-vav; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D020218:Response Elements / Q000187:drug effects / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D011948:Receptors, Antigen, T-Cell; D018808:Transcription Factor AP-1; D014157:Transcription Factors; C496618:VAV1 protein, human; D007371:Interferon-gamma; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020741:rho GTP-Binding Proteins