A Novel Intronic cAMP Response Element Modulator (CREM) Promoter Is Regulated by Activator Protein-1 (AP-1) and Accounts for Altered Activation-induced CREM Expression in T Cells from Patients with Systemic Lupus Erythematosus

• Published in: The Journal of biological chemistry Vol. 286; no. 37; pp. 32366 - 32372
• Main Authors: Rauen, Thomas, Benedyk, Konrad, Juang, Yuang-Taung, Kerkhoff, Claus, Kyttaris, Vasileios C., Roth, Johannes, Tsokos, George C., Tenbrock, Klaus
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16-09-2011; American Society for Biochemistry and Molecular Biology
• Subjects: AP-1 Transcription Factor; Carcinogens - pharmacology; CD28 Antigens - genetics; CD28 Antigens - metabolism; CD3 Complex - genetics; CD3 Complex - metabolism; CREM; Cyclic AMP Response Element Modulator - genetics; Cyclic AMP Response Element Modulator - metabolism; Exons - genetics; Gene Regulation; Humans; Immunology; Interleukin; Ionomycin - pharmacology; Ionophores - pharmacology; Lupus; Lupus Erythematosus, Systemic - metabolism; Lupus Erythematosus, Systemic - pathology; Lymphocyte Activation; Promoters; Proto-Oncogene Proteins c-fos - genetics; Proto-Oncogene Proteins c-fos - metabolism; SLE; T-Lymphocytes - metabolism; T-Lymphocytes - pathology; Tetradecanoylphorbol Acetate - pharmacology; Transcription Factor AP-1 - genetics; Transcription Factor AP-1 - metabolism; Transcription Factors; Up-Regulation; Lupus; Immunology; Interleukin; CREM; Transcription Factors; AP-1 Transcription Factor; SLE; Promoters
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.245811

The transcriptional repressor cAMP response element modulator (CREM) α has important roles in normal T cell physiology and contributes to aberrant T cell function in patients with systemic lupus erythematosus (SLE). Recently, we characterized a specificity protein-1-dependent promoter located upstream of the CREM gene that accounts for increased basal CREM expression in SLE T cells and reflects disease activity. Here, we identify a novel intronic CREM promoter (denoted P2) in front of the second exon of the CREM gene that harbors putative binding sites for TATA-binding proteins and the transcriptional activator AP-1. DNA binding studies, chromatin immunoprecipitation, and reporter assays confirmed the functional relevance of these sites, and T cell activation through CD3/CD28 stimulation or phorbol 12-myristate 13-acetate/ionomycin treatment enhances P2 promoter activity. Although the basal CREM levels are increased in T cells from SLE patients compared with healthy controls, there are remarkable differences in the regulation of CREM expression in response to T cell activation. Whereas T cells from healthy individuals display increased CREM expression after T cell activation, most likely through AP-1-dependent up-regulation of the P2 promoter, SLE T cells fail to further increase their basal CREM levels upon T cell activation due to a decreased content of the AP-1 family member c-Fos. Because CREM trans-represses c-fos transcription in SLE T cells, we propose an autoregulatory feedback mechanism between CREM and AP-1. Our findings extend the understanding of CREM gene regulation in the context of T cell activation and disclose another difference in the transcriptional machinery in SLE T cells.