Mora-López Francisco, Reales Elena, Brieva José A, Campos-Caro Antonio
Unidad de Investigación, Hospital Universitario Puerta del Mar, Avenida Ana de Viya 21, 11009 Cádiz, Spain.
Blood. 2007 Nov 1;110(9):3150-7. doi: 10.1182/blood-2007-05-092262. Epub 2007 Aug 6.
B-lymphocyte-induced maturation protein-1 (BLIMP1), encoded by the PRDM1 gene, is a transcriptional repressor considered a master regulator that is required and sufficient for plasma cell (PC) differentiation. BLIMP1 represses the PAX5 gene, coding for the B-cell lineage-specific activator protein (BSAP), which is required for B-cell identity and survival. Mutations in PAX5 gene as well as in PRDM1 gene have been recently implicated in lymphomas. In the present study, sequence analysis of PRDM1 gene revealed a binding site for BSAP transcription factor. By analyzing different human cell lines, we have found that a specific nuclear factor for B-cell lines binds to a site on the PRDM1 promoter. Electrophoretic mobility shift assays identified this factor as BSAP, and chromatin immunoprecipitation assays confirmed its binding in vivo to the human PRDM1 promoter. Moreover, by ectopically expressing BSAP, and using a PRDM1 promoter with the BSAP-binding site mutated, we demonstrated that this factor represses the expression of BLIMP1. Therefore, repression of PRDM1 by BSAP reveals an autoregulatory negative-feedback loop that could play a relevant role in controlling human PC differentiation.
由PRDM1基因编码的B淋巴细胞诱导成熟蛋白1（BLIMP1）是一种转录抑制因子，被认为是浆细胞（PC）分化所必需且足够的主要调节因子。BLIMP1抑制PAX5基因，该基因编码B细胞谱系特异性激活蛋白（BSAP），而B细胞的特性和存活需要BSAP。最近发现PAX5基因以及PRDM1基因的突变与淋巴瘤有关。在本研究中，PRDM1基因的序列分析揭示了一个BSAP转录因子的结合位点。通过分析不同的人类细胞系，我们发现一种B细胞系特异性核因子与PRDM1启动子上的一个位点结合。电泳迁移率变动分析确定该因子为BSAP，染色质免疫沉淀分析证实其在体内与人PRDM1启动子结合。此外，通过异位表达BSAP，并使用BSAP结合位点突变的PRDM1启动子，我们证明该因子抑制BLIMP1的表达。因此，BSAP对PRDM1的抑制揭示了一个自动调节的负反馈环，该负反馈环可能在控制人类PC分化中发挥相关作用。
