title: 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.
abstract: 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.
authors.affiliation: Division of Rheumatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rauen
authors.forename: Konrad
authors.initials: K
authors.lastname: Benedyk
authors.forename: Yuang-Taung
authors.initials: YT
authors.lastname: Juang
authors.forename: Claus
authors.initials: C
authors.lastname: Kerkhoff
authors.forename: Vasileios C
authors.initials: VC
authors.lastname: Kyttaris
authors.forename: Johannes
authors.initials: J
authors.lastname: Roth
authors.forename: George C
authors.initials: GC
authors.lastname: Tsokos
authors.forename: Klaus
authors.initials: K
authors.lastname: Tenbrock
mesh_terms: D018106:CD28 Antigens / Q000235:genetics / Q000378:metabolism; D017252:CD3 Complex / Q000235:genetics / Q000378:metabolism; D002273:Carcinogens / Q000494:pharmacology; D051786:Cyclic AMP Response Element Modulator / Q000235:genetics / Q000378:metabolism*; D005091:Exons / Q000235:genetics; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D008180:Lupus Erythematosus, Systemic / Q000378:metabolism* / Q000473:pathology; D008213:Lymphocyte Activation; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D018106:CD28 Antigens; D017252:CD3 Complex; C497410:CREM protein, human; D002273:Carcinogens; D007476:Ionophores; D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1; D051786:Cyclic AMP Response Element Modulator; D015759:Ionomycin; D013755:Tetradecanoylphorbol Acetate