Aleksic T, Bechtel M, Krndija D, von Wichert G, Knobel B, Giehl K, Gress T M, Michl P
Department of Internal Medicine I, University of Ulm, Ulm, Germany.
Oncogene. 2007 Aug 30;26(40):5939-49. doi: 10.1038/sj.onc.1210398. Epub 2007 Mar 19.
Recently, we identified the homeodomain transcription factor CUTL1 as important mediator of cell migration and tumor invasion downstream of transforming growth factor beta (TGFbeta). The molecular mechanisms and effectors mediating the pro-migratory and pro-invasive phenotype induced by CUTL1 have not been elucidated so far. Therefore, the aim of this study was to identify signaling pathways downstream of CUTL1 which are responsible for its effects on tumor cell migration. We found that the reduced motility seen after knock down of CUTL1 by RNA interference is accompanied by a delay in tumor cell spreading. This spreading defect is paralleled by a marked reduction of Src protein levels. We show that CUTL1 leads to Src protein stabilization and activation of Src-regulated downstream signaling molecules such as RhoA, Rac1, Cdc42 and ROCK. In addition, we demonstrate that CUTL1 decreases proteasome-mediated Src protein degradation, possibly via transcriptionally upregulating C-terminal Src kinase (Csk). Based on experiments using Src knockout cells (SYF), we present evidence that Src plays a crucial role in CUTL1-induced tumor cell migration. In conclusion, our findings linking the pro-invasive transcription factor CUTL1 and the Src pathway provide important new insights in the molecular effector pathways mediating CUTL-induced migration and invasion.
最近，我们确定了同源结构域转录因子CUTL1是转化生长因子β（TGFβ）下游细胞迁移和肿瘤侵袭的重要介质。迄今为止，介导CUTL1诱导的促迁移和促侵袭表型的分子机制和效应器尚未阐明。因此，本研究的目的是确定CUTL1下游负责其对肿瘤细胞迁移作用的信号通路。我们发现，通过RNA干扰敲低CUTL1后观察到的运动性降低伴随着肿瘤细胞铺展延迟。这种铺展缺陷与Src蛋白水平的显著降低同时出现。我们表明，CUTL1导致Src蛋白稳定并激活Src调节的下游信号分子，如RhoA、Rac1、Cdc42和ROCK。此外，我们证明CUTL1可能通过转录上调C末端Src激酶（Csk）来减少蛋白酶体介导的Src蛋白降解。基于使用Src基因敲除细胞（SYF）的实验，我们提供证据表明Src在CUTL1诱导的肿瘤细胞迁移中起关键作用。总之，我们将促侵袭转录因子CUTL1与Src途径联系起来的研究结果为介导CUTL诱导的迁移和侵袭的分子效应途径提供了重要的新见解。
