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: Thomas Rauen, Konrad Benedyk, Yuang-Taung Juang, Claus Kerkhoff, Vasileios C Kyttaris, Johannes Roth, George C Tsokos, Klaus Tenbrock
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 286 Issue 37 Pg. 32366-72 (Sep 16 2011) ISSN: 1083-351X [Electronic] United States
• PMID: 21757709 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CD28 Antigens
• CD3 Complex
• CREM protein, human
• Carcinogens
• Ionophores
• Proto-Oncogene Proteins c-fos
• Transcription Factor AP-1
• Cyclic AMP Response Element Modulator
• Ionomycin
• Tetradecanoylphorbol Acetate

Topics

• CD28 Antigens (genetics, metabolism)
• CD3 Complex (genetics, metabolism)
• Carcinogens (pharmacology)
• Cyclic AMP Response Element Modulator (genetics, metabolism)
• Exons (genetics)
• Humans
• Ionomycin (pharmacology)
• Ionophores (pharmacology)
• Lupus Erythematosus, Systemic (metabolism, pathology)
• Lymphocyte Activation
• Proto-Oncogene Proteins c-fos (genetics, metabolism)
• T-Lymphocytes (metabolism, pathology)
• Tetradecanoylphorbol Acetate (pharmacology)
• Transcription Factor AP-1 (genetics, metabolism)
• Up-Regulation