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

FEBS Lett. 2002 Mar 13;514(2-3):153-8. doi: 10.1016/s0014-5793(02)02316-5.

Abstract

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.

MeSH terms

  • DNA-Binding Proteins / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Activation / drug effects
  • Gene Expression / drug effects
  • Genes, Reporter
  • Humans
  • Interferon-gamma / genetics*
  • JNK Mitogen-Activated Protein Kinases
  • Jurkat Cells / metabolism
  • Mitogen-Activated Protein Kinases / metabolism
  • NFATC Transcription Factors
  • Nuclear Proteins*
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism*
  • Oncogene Proteins / pharmacology
  • Promoter Regions, Genetic / drug effects
  • Promoter Regions, Genetic / physiology*
  • Proto-Oncogene Proteins c-vav
  • Receptors, Antigen, T-Cell / metabolism
  • Response Elements / drug effects
  • Response Elements / physiology
  • Transcription Factor AP-1 / metabolism*
  • Transcription Factors / metabolism
  • Transfection
  • Up-Regulation / drug effects
  • Up-Regulation / physiology*
  • rho GTP-Binding Proteins / metabolism

Substances

  • DNA-Binding Proteins
  • NFATC Transcription Factors
  • Nuclear Proteins
  • Oncogene Proteins
  • Proto-Oncogene Proteins c-vav
  • Receptors, Antigen, T-Cell
  • Transcription Factor AP-1
  • Transcription Factors
  • VAV1 protein, human
  • Interferon-gamma
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • rho GTP-Binding Proteins