Pax-5 (BSAP) recruits Ets proto-oncogene family proteins to form functional ternary complexes on a B-cell-specific promoter
Pax-5 (BSAP) recruits Ets proto-oncogene family proteins to form functional ternary complexes on a B-cell-specific promoter
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DOI：
10.1101/gad.10.17.2198
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发表时间：
1996-09-01
影响因子：
10.5
通讯作者：
Hagman, J
中科院分区：
文献类型：
--
作者：
Fitzsimmons, D;Hodsdon, W;Hagman, J
配对盒转录因子Pax-5（B细胞特异性激活蛋白）是B淋巴细胞中谱系特异性基因表达和分化的关键调节因子。我们表明，Pax-5的功能作为一个细胞类型特异性的对接蛋白，促进早期B细胞特异性MB-1启动子的结合蛋白的Ets原癌基因家族。mb-1启动子在前B细胞中的转录活性严重依赖于Pax-5：Ets复合物的结合位点。三元复合物组装仅需要Pas-5配对盒和ETS DNA结合结构域。在三元复合物结合位点中的单个碱基对的突变允许Ets蛋白的独立结合，但相反地，抑制Pax-5自身的结合。引人注目的是，这种突变逆转了复杂装配的模式：Ets蛋白招募Pax-5来结合突变的序列。招聘净酸Elk-1，但不是SAP 1a，由Pax-5定义了密切相关的Ets蛋白之间的功能差异。天冬氨酸（如c-Ets-1，Elk-1和Net中所发现的）取代SAP 1a ETS结构域中的缬氨酸（V68）可使三元复合物的形成增加60倍以上。总之，这些观察结果定义了新的转录因子相互作用，调节B细胞中的基因表达。
The paired box transcription factor Pax-5 (B-cell-specific activator protein) is a key regulator of lineage-specific gene expression and differentiation in B-lymphocytes. We show that Pax-5 functions as a cell type-specific docking protein that facilitates binding of the early B-cell-specific mb-1 promoter by proteins of the Ets proto-oncogene family. Transcriptional activity of the mb-1 promoter in pre-B-cells is critically dependent on binding sites for Pax-5:Ets complexes. Ternary complex assembly requires only the Pas-5 paired box and ETS DNA-binding domains. Mutation of a single base pair in the ternary complex binding site allows for independent binding by Ets proteins but, conversely, inhibits the binding of Pax-5 by itself. Strikingly, the mutation reverses the pattern of complex assembly: Ets proteins recruit Pax-5 to bind the mutated sequence. Recruitment of Net acid Elk-1, but not SAP1a, by Pax-5 defines a functional difference between closely related Ets proteins. Replacement of a valine (V68) in the ETS domain of SAP1a by aspartic acid (as found in c-Ets-1, Elk-1, and Net) enhanced ternary complex formation by more than 60-fold. Together, these observations define novel transcription factor interactions that regulate gene expression in B cells.