MHC class I gene expression is negatively regulated by the proto-oncogene, c-jun

Area of Science:

• Molecular Biology
• Immunology
• Gene Regulation

Background:

• The activator protein 1 (AP-1) is a transcription factor complex regulating gene expression.
• AP-1 binding sites are present in the regulatory regions of major histocompatibility complex (MHC) class I genes.
• The in vivo role of AP-1 in MHC class I gene regulation remained uninvestigated.

Purpose of the Study:

• To investigate the role of AP-1, specifically c-Jun, in the regulation of MHC class I gene transcription in vivo.
• To identify the c-Jun responsive element within the MHC class I gene regulatory region.

Main Methods:

• Cotransfection assays using an MHC class I reporter construct and a c-Jun expression construct.
• Functional and direct binding assays with purified c-Jun to identify the responsive element.
• Quantitative analysis of endogenous MHC class I RNA levels following c-Jun overexpression.

Main Results:

• Expression of c-Jun led to a significant decrease in MHC class I promoter activity.
• A specific c-Jun responsive element was identified between base pairs -440 and -431 upstream of the transcription start site.
• Overexpression of c-Jun resulted in a 10-fold reduction in steady-state levels of endogenous MHC class I RNA.

Conclusions:

• The c-Jun/AP-1 complex functions as a negative trans-acting factor.
• c-Jun actively down-regulates the transcription of MHC class I genes in vivo.