Institute of Physiological Chemistry, University Ulm, D-89081 Ulm, Germany, Institute of Pathology, University Ulm, D-89081 Ulm, Germany.
Nucleic Acids Res. 2013 Feb 1;41(4):2138-54. doi: 10.1093/nar/gks1349. Epub 2013 Jan 4.
The transcriptional co-activator BOB.1/OBF.1 was originally identified in B cells and is constitutively expressed throughout B cell development. BOB.1/OBF.1 associates with the transcription factors Oct1 and Oct2, thereby enhancing octamer-dependent transcription. In contrast, in T cells, BOB.1/OBF.1 expression is inducible by treatment of cells with PMA/Ionomycin or by antigen receptor engagement, indicating a marked difference in the regulation of BOB.1/OBF.1 expression in B versus T cells. The molecular mechanisms underlying the differential expression of BOB.1/OBF.1 in T and B cells remain largely unknown. Therefore, the present study focuses on mechanisms controlling the transcriptional regulation of BOB.1/OBF.1 and Oct2 in T cells. We show that both calcineurin- and NF-κB-inhibitors efficiently attenuate the expression of BOB.1/OBF.1 and Oct2 in T cells. In silico analyses of the BOB.1/OBF.1 promoter revealed the presence of previously unappreciated combined NFAT/NF-κB sites. An array of genetic and biochemical analyses illustrates the involvement of the Ca(2+)/calmodulin-dependent phosphatase calcineurin as well as NFAT and NF-κB transcription factors in the transcriptional regulation of octamer-dependent transcription in T cells. Conclusively, impaired expression of BOB.1/OBF.1 and Oct2 and therefore a hampered octamer-dependent transcription may participate in T cell-mediated immunodeficiency caused by the deletion of NFAT or NF-κB transcription factors.
转录共激活因子 BOB.1/OBF.1 最初在 B 细胞中被鉴定出来，并且在 B 细胞发育过程中持续表达。BOB.1/OBF.1 与转录因子 Oct1 和 Oct2 结合，从而增强八聚体依赖的转录。相比之下，在 T 细胞中，BOB.1/OBF.1 的表达可通过用 PMA/离子霉素处理细胞或通过抗原受体结合来诱导，表明在 B 细胞和 T 细胞中 BOB.1/OBF.1 表达的调节有明显差异。在 T 和 B 细胞中 BOB.1/OBF.1 表达差异的分子机制在很大程度上仍然未知。因此，本研究集中于控制 T 细胞中 BOB.1/OBF.1 和 Oct2 转录调控的机制。我们表明，钙调神经磷酸酶和 NF-κB 抑制剂均可有效抑制 T 细胞中 BOB.1/OBF.1 和 Oct2 的表达。对 BOB.1/OBF.1 启动子的计算机分析揭示了以前未被认识到的 NFAT/NF-κB 联合结合位点的存在。一系列遗传和生化分析表明，Ca(2+)/钙调蛋白依赖性磷酸酶钙调神经磷酸酶以及 NFAT 和 NF-κB 转录因子参与了 T 细胞中八聚体依赖转录的转录调控。总之，BOB.1/OBF.1 和 Oct2 的表达受损，因此八聚体依赖的转录受阻，可能参与了 NFAT 或 NF-κB 转录因子缺失引起的 T 细胞介导的免疫缺陷。
