A Complex of Nuclear Factor I-X3 and STAT3 Regulates Astrocyte and Glioma Migration through the Secreted Glycoprotein YKL-40
A Complex of Nuclear Factor I-X3 and STAT3 Regulates Astrocyte and Glioma Migration through the Secreted Glycoprotein YKL-40
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DOI：
10.1074/jbc.m111.257451
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发表时间：
2011-11-18
影响因子：
4.8
通讯作者：
Kordula, Tomasz
中科院分区：
文献类型：
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作者：
Singh, Sandeep K.;Bhardwaj, Reetika;Kordula, Tomasz
核因子I-X3（NFI-X3）是一种新发现的NFI-X剪接变异体，可调节几种星形胶质细胞特异性标志物的表达，如胶质细胞酸性蛋白。在这里，我们确定了一组由NFI-X3调控的基因，其中包括编码分泌型糖蛋白YKL-40的基因。虽然YKL-40的表达在多形性胶质母细胞瘤中上调，但其在中枢神经系统非转化细胞中的调节和功能尚未被广泛探索。我们发现YKL-40的表达在脑发育过程中被激活，并且在体外神经祖细胞向星形胶质细胞的分化过程中也被激活。此外，YKL-40是原代星形胶质细胞的迁移因子，其表达受NFI-X3和STAT 3控制，这两种因子是已知的胶质细胞生成调节因子。敲低NFI-X3和STAT 3显著降低星形胶质细胞中YKL-40的表达，而过表达NFI-X3显著增强胶质瘤细胞中YKL-40的表达。抑瘤素M激活STAT 3可诱导星形胶质细胞中YKL-40的表达，而显性负性STAT 3的表达具有抑制作用。在机制上，NFI-X3和STAT 3形成复合物，其结合YKL-40启动子中的弱调控元件并激活转录。我们认为NFI-X3和STAT 3通过调控YKL-40的表达来调控分化中的星形胶质细胞的迁移以及胶质瘤细胞的迁移和侵袭。
Nuclear factor I-X3 (NFI-X3) is a newly identified splice variant of NFI-X that regulates expression of several astrocyte-specific markers, such as glial fibrillary acidic protein. Here, we identified a set of genes regulated by NFI-X3 that includes a gene encoding a secreted glycoprotein YKL-40. Although YKL-40 expression is up-regulated in glioblastoma multiforme, its regulation and functions in nontransformed cells of the central nervous system are widely unexplored. We find that expression of YKL-40 is activated during brain development and also differentiation of neural progenitors into astrocytes in vitro. Furthermore, YKL-40 is a migration factor for primary astrocytes, and its expression is controlled by both NFI-X3 and STAT3, which are known regulators of gliogenesis. Knockdown of NFI-X3 and STAT3 significantly reduced YKL-40 expression in astrocytes, whereas overexpression of NFI-X3 dramatically enhanced YKL-40 expression in glioma cells. Activation of STAT3 by oncostatin M induced YKL-40 expression in astrocytes, whereas expression of a dominant-negative STAT3 had a suppressive effect. Mechanistically, NFI-X3 and STAT3 form a complex that binds to weak regulatory elements in the YKL-40 promoter and activates transcription. We propose that NFI-X3 and STAT3 control the migration of differentiating astrocytes as well as migration and invasion of glioma cells via regulating YKL-40 expression.