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*
- ‡Hospital for Special Surgery, Research Division, New York, the §Weill Medical College of Cornell University, Department of Medicine, Division of Rheumatology, New York, and the ¶Weill Graduate School of Medical Sciences, Immunology Program, New York, New York 10021
- 1 To whom correspondence should be addressed: Research Division, Hospital for Special Surgery, 535 East 70th St., New York, NY 10021. Tel.: 212-774-2390; Fax: 212-774-2337; E-mail: pricopl{at}hss.edu.
Abstract
The inhibitory receptor FcγRIIb 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 FcγRIIb 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.
Footnotes
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↵2 The abbreviations used are: FcγR, Fc γ-receptors; SNP, single nucleotide polymorphism; SLE, systemic lupus erythematosus; AP-1, activating protein 1; YY1, Yin-Yang 1; JNK, Jun N-terminal kinase; MEKK, mitogen-activated/extracellular signal-regulated kinase kinase kinase; EMSA, electrophortic mobility shift assay; ChIP, chromatin immunoprecipitation; shRNA, short hairpin RNA; PMA, phorbol 12-myristate 13-acetate; ION, ionomycin; WT, wild type; Bt2cAMP, dibutyryl-cAMP.
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↵* This work was supported by National Institutes of Health Grant AR49765, the Lupus Research Institute, the Mary Kirkland Lupus Center, and the Arthritis Foundation (to L. P.). This work was conducted in a facility constructed with support from Research Facilities Improvement Program Grant C06-RR12538-01 from the National Center for Research Resources, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵† This article is dedicated to the memory of Shizuko Tanaka.
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- Received June 16, 2006.
- Revision received November 2, 2006.
- The American Society for Biochemistry and Molecular Biology, Inc.
