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
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
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DOI：
10.1074/jbc.m111.245811
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发表时间：
2011-09-16
影响因子：
4.8
通讯作者：
Tenbrock, Klaus
中科院分区：
文献类型：
--
作者：
Rauen, Thomas;Benedyk, Konrad;Tenbrock, Klaus
转录抑制因子cAMP反应元件调节剂（CREM）α在正常T细胞生理学中具有重要作用，并导致系统性红斑狼疮（SLE）患者的异常T细胞功能。最近，我们表征了位于CREM基因上游的特异性蛋白-1依赖性启动子，该启动子导致SLE T细胞中CREM基础表达增加并反映疾病活动。在这里，我们确定了一个新的内含子CREM启动子（表示P2）的CREM基因的第二个外显子，窝藏TATA结合蛋白和转录激活因子AP-1的推定结合位点的前面。DNA结合的研究，染色质免疫沉淀，和记者测定证实了这些网站的功能相关性，和T细胞活化通过CD 3/CD 28刺激或佛波醇12-肉豆蔻酸酯13-乙酸酯/离子霉素治疗增强P2启动子活性。虽然与健康对照相比，SLE患者的T细胞中的基础CREM水平增加，但在响应于T细胞活化的CREM表达的调节中存在显著差异。而来自健康个体的T细胞在T细胞活化后显示增加的CREM表达，最可能是通过P2启动子的AP-1依赖性上调，SLE T细胞在T细胞活化后由于AP-1家族成员c-Fos含量降低而未能进一步增加其基础CREM水平。由于CREM反式抑制SLE T细胞中的c-fos转录，我们提出CREM和AP-1之间的自动调节反馈机制。我们的研究结果扩展了对CREM基因在T细胞活化背景下调控的理解，并揭示了SLE T细胞转录机制的另一个差异。
The transcriptional repressor cAMP response element modulator (CREM) alpha 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.