Spi-1 and Spi-B control the expression of the Grap2 gene in B cells
Spi-1 and Spi-B control the expression of the Grap2 gene in B cells
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DOI：
10.1016/j.gene.2005.04.009
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发表时间：
2005-06-20
期刊：
影响因子：
3.5
通讯作者：
Clark, MR
中科院分区：
文献类型：
--
作者：
Garrett-Sinha, LA;Hou, P;Clark, MR
Ets 家族成员 Spi-1 和 Spi-B 参与了对 B 细胞抗原受体 (BCR) 信号转导重要的基因的调节。 Spi-B 缺陷的小鼠表现出响应 BCR 交联的 B 细胞增殖减少和 T 细胞依赖性免疫反应受损。当 Spi-1 单倍体不足 (Spi1(+/-)SpiB(-/-)) 时，这种缺陷会加剧。尽管表达了许多关键的 BCR 信号蛋白，但 BCR 参与诱导的酪氨酸磷酸化和钙动员在 Spi1(+/-)SpiB(-/-) B 淋巴细胞中减弱，这表明 Spi-1 和 Spi-B 调节其他未识别信号分子的表达。我们现在证明接头蛋白 Grap2 的表达在 Spi1(+/-)SpiB(+/-) 和 Spi1(+/-)SpiB(-/-) B 淋巴细胞中受损。对两个备用鼠 Grap2 启动子的分析揭示了位于下游启动子的功能重要的 Spi-1 和 Spi-B DNA 结合元件。 Grap2 缺陷 B 细胞中 Grap2 的异位表达减少了 BLNK 向 Ig α 的募集以及特定底物的磷酸化。 BLNK 招募的调节取决于 Grap2 富含脯氨酸的结构域，而磷酸化的调节则取决于富含脯氨酸和 SH2 结构域。这些数据表明 Spi-1 和 Spi-B 直接调节 Grap2 的表达，并且 Grap2 的功能是调节 BCR 信号传导，但 Grap2 表达的减少不太可能解释在 Spi(+/-)SpiB(-/-) B 细胞中观察到的 BCR 信号传导缺陷。 (c) 2005 Elsevier B.V. 保留所有权利。
The Ets family members Spi-1 and Spi-B have been implicated in the regulation of genes important for B cell antigen receptor (BCR) signaling. Mice deficient in Spi-B exhibit reduced B cell proliferation in response to BCR cross-linking and impaired T cell-dependent immune responses. This defect is exacerbated in the presence of Spi-1 haplo-insufficiency (Spi1(+/-)SpiB(-/-)). Tyrosine phosphorylation and calcium mobilization induced by BCR engagement is diminished in Spi1(+/-)SpiB(-/-) B lymphocytes, although many key BCR signaling proteins are expressed, suggesting that Spi-1 and Spi-B regulate expression of additional, unidentified signaling molecules. We now demonstrate that expression of the adaptor protein Grap2 is impaired in Spi1(+/-)SpiB(+/-) and Spi1(+/-)SpiB(-/-) B lymphocytes. Analysis of two alternate murine Grap2 promoters revealed a functionally important Spi-1 and Spi-B DNA binding element located in the downstream promoter. Ectopic expression of Grap2 in Grap2-deficient B cells reduced the recruitment of BLNK to Ig alpha and the phosphorylation of specific substrates. Regulation of BLNK recruitment was dependent upon the Grap2 proline-rich domain, while modulation of phosphorylation was dependent upon both the proline-rich and SH2 domains. These data indicate that Spi-1 and Spi-B directly regulate the expression of Grap2 and that Grap2 functions to modulate BCR signaling, but that reduced Grap2 expression is unlikely to account for the BCR signaling defects observed in Spi(+/-)SpiB(-/-) B cells. (c) 2005 Elsevier B.V. All rights reserved.