LMO4 can interact with Smad proteins and modulate transforming growth factor-β signaling in epithelial cells
LMO4 can interact with Smad proteins and modulate transforming growth factor-β signaling in epithelial cells
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DOI：
10.1038/sj.onc.1209318
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发表时间：
2006-05-01
期刊：
影响因子：
8
通讯作者：
Andersen, B.
中科院分区：
文献类型：
--
作者：
Lu, Z.;Lam, K. S.;Andersen, B.
LIM蛋白4（LMO 4）在哺乳动物的发育过程中起着关键作用，并被认为在上皮肿瘤发生中起作用，包括乳腺癌。由于LMO 4在活跃的间充质-上皮相互作用的位置处的上皮区室中高度表达，我们推断LMO 4可能通过调节间充质-上皮信号传导中涉及的信号传导途径起作用。一种这样的候选信号是转化生长因子-β（TGF β）细胞因子途径，其在发育和癌症中起重要作用。我们在此表明，上皮细胞中对TGF β的转录应答对LMO 4水平敏感; LMO 4的上调和下调均可增强TGF β信号传导，如TGF β应答报告基因所评估。此外，LMO 4可与受体介导的Smad蛋白的MH 1和接头结构域相互作用，并以TGF β依赖性方式与内源性TGF β-响应性纤溶酶原激活物抑制剂-1基因启动子结合，表明这种相互作用可介导LMO 4对TGF β信号传导的作用.当导入乳腺上皮细胞时，LMO 4增强了TGF β在这些细胞中的生长抑制作用。这些结果德。LMO 4作为TGF β信号传导的共激活剂的新功能，并为LMO 4介导的发育和肿瘤发生的调节提供了潜在的新机制。
LIM- only protein 4 ( LMO4) plays critical roles in mammalian development, and has been proposed to play roles in epithelial oncogenesis, including breast cancer. As LMO4 is highly expressed in the epithelial compartments at locations of active mesenchymal - epithelial interactions, we reasoned that LMO4 might act by modulating signaling pathways involved in mesenchymal - epithelial signaling. One such candidate signal is the transforming growth factor- beta ( TGF beta) cytokine pathway, which plays important roles both in development and cancer. We show here that the transcriptional response to TGFb in epithelial cells is sensitive to LMO4 levels; both up- and downregulation of LMO4 can enhance TGF beta signaling as assessed by a TGF beta- responsive reporter gene. Furthermore, LMO4 can interact with the MH1 and linker domains of receptor- mediated Smad proteins, and associate with the endogenous TGF beta- responsive Plasminogen Activator Inhibitor- 1 gene promoter in a TGF beta- dependent manner, suggesting that such interactions may mediate the effects of LMO4 on TGFb signaling. When introduced into mammary epithelial cells, LMO4 potentiated the growth- inhibitory effects of TGF beta in those cells. These results de. ne a new function for LMO4 as a coactivator in TGFb signaling, and provide a potential novel mechanism for LMO4- mediated regulation in development and oncogenesis.