The role of activating protein 1 in the transcriptional regulation of the human FCGR2B promoter mediated by the -343 G -> C polymorphism associated with systemic lupus erythematosus.
The inhibitory receptor FcgammaRIIb is a negative regulator of antibody production and inflammatory responses. The -343 G --> C polymorphism in the human FCGR2B promoter is associated with systemic lupus erythematosus. The -343 C mutant promoter has decreased transcriptional activity. In the present study, we show that the transcriptional change correlates with quantitative differences in the interaction of the activating protein 1 complex with the mutant FCGR2B promoter. Promoter pulldown and chromatin immunoprecipitation assays demonstrated binding of c-Jun to the FCGR2B promoter. Phosphorylation of c-Jun was accompanied by transactivation of both FCGR2B promoter variants, whereas dephosphorylation of c-Jun by an inhibitor of c-Jun N-terminal kinase, markedly decreased the promoter activities. The -343 G --> C substitution enabled the specific interaction of the transcription factor Yin-Yang 1 with the mutant FCGR2B promoter. Yin-Yang 1 competed with activating protein 1 for binding at the -343 site, and contributed to the repression of the mutant FCGR2B promoter activity. This mechanism could be responsible for the decreased expression of FcgammaRIIb associated with the -343 C/C homozygous FCGR2B genotype in lupus patients. These findings provide a rationale for the transcriptional defect mediated by the -343 C/C FCGR2B promoter polymorphism associated with systemic lupus erythematosus, and add to our understanding of the complex transcriptional regulation of the human FCGR2B promoter.
Olferiev
Mikhail
M
Hospital for Special Surgery, Research Division, New York, USA.
Masuda
Emi
E
Tanaka
Shizuko
S
Blank
Marissa C
MC
Pricop
Luminita
L
D001483:Base Sequence; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008954:Models, Biological; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D017452:Receptors, IgG / Q000235:genetics*; D018808:Transcription Factor AP-1 / Q000502:physiology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D020298:U937 Cells
C499173:FCGR2B protein, human; D017452:Receptors, IgG; D018808:Transcription Factor AP-1