PDF(Pubmed)
Abstract：
SALL2/Sall2 is a transcription factor associated with development, neuronal differentiation, and cancer. Interestingly, SALL2/Sall2 deficiency leads to failure of the optic fissure closure and neurite outgrowth, suggesting a positive role for SALL2/Sall2 in cell migration. However, in some cancer cells, SALL2 deficiency is associated with increased cell migration. To further investigate the role of Sall2 in the cell migration process, we used immortalized Sall2 knockout (Sall2 -/- ) and Sall2 wild-type (Sall2 +/+ ) mouse embryonic fibroblasts (iMEFs). Our results indicated that Sall2 positively regulates cell migration, promoting cell detachment and focal adhesions turnover. Sall2 deficiency decreased cell motility and altered focal adhesion dynamics. Accordingly, restoring Sall2 expression in the Sall2 -/- iMEFs by using a doxycycline-inducible Tet-On system recovered cell migratory capabilities and focal adhesion dynamics. In addition, Sall2 promoted the autophosphorylation of Focal Adhesion Kinase (FAK) at Y397 and increased integrin β1 mRNA and its protein expression at the cell surface. We demonstrated that SALL2 increases ITGB1 promoter activity and binds to conserved SALL2-binding sites at the proximal region of the ITGB1 promoter, validated by ChIP experiments. Furthermore, the overexpression of integrin β1 or its blockade generates a cell migration phenotype similar to that of Sall2 +/+ or Sall2 -/- cells, respectively. Altogether, our data showed that Sall2 promotes cell migration by modulating focal adhesion dynamics, and this phenotype is associated with SALL2/Sall2-transcriptional regulation of integrin β1 expression and FAK autophosphorylation. Since deregulation of cell migration promotes congenital abnormalities, tumor formation, and spread to other tissues, our findings suggest that the SALL2/Sall2-integrin β1 axis could be relevant for those processes.
摘要：
SALL2/Sall2是与发育有关的转录因子，神经元分化，和癌症。有趣的是,SALL2/Sall2缺乏导致视裂闭合失败和神经突生长。提示SALL2/Sall2在细胞迁移中的积极作用。然而,在一些癌细胞中，SALL2缺乏与细胞迁移增加有关。为了进一步研究Sall2在细胞迁移过程中的作用，我们使用了永生化的Sall2基因敲除(Sall2-/-)和Sall2野生型(Sall2+/+)小鼠胚胎成纤维细胞(iMEFs)。我们的结果表明，Sall2正调节细胞迁移，促进细胞脱离和粘着斑更新。Sall2缺乏降低了细胞运动并改变了粘着斑动力学。因此，通过使用多西环素诱导的Tet-On系统恢复Sall2-/-iMEFs中的Sall2表达，恢复了细胞迁移能力和局灶性粘附动力学。此外,Sall2促进了Y397上粘着斑激酶（FAK）的自磷酸化，并增加了整合素β1mRNA及其在细胞表面的蛋白质表达。我们证明SALL2增加了ITGB1启动子的活性，并与ITGB1启动子近端的保守的SALL2结合位点结合，通过ChIP实验验证。此外，整合素β1的过表达或其阻断产生类似于Sall2+/+或Sall2-/-细胞的细胞迁移表型，分别。总之,我们的数据显示Sall2通过调节局灶性粘附动力学促进细胞迁移，这种表型与SALL2/Sall2转录调节整联蛋白β1表达和FAK自磷酸化有关。由于细胞迁移的失调会促进先天性异常，肿瘤形成，并扩散到其他组织，我们的研究结果表明,SALL2/Sall2-整合素β1轴可能与这些过程相关.
