Escrivà Maria, Peiró Sandra, Herranz Nicolás, Villagrasa Patricia, Dave Natàlia, Montserrat-Sentís Bàrbara, Murray Stephen A, Francí Clara, Gridley Thomas, Virtanen Ismo, García de Herreros Antonio
Institut Municipal d'Investigació Mèdica, Parc de Recerca Biomèdica de Barcelona, c/Dr. Aiguader 88, E-08003 Barcelona, Spain.
Mol Cell Biol. 2008 Mar;28(5):1528-40. doi: 10.1128/MCB.02061-07. Epub 2008 Jan 2.
The product of the Snail1 gene is a transcriptional repressor required for triggering the epithelial-to-mesenchymal transition. Furthermore, ectopic expression of Snail1 in epithelial cells promotes resistance to apoptosis. In this study, we demonstrate that this resistance to gamma radiation-induced apoptosis caused by Snail1 is associated with the inhibition of PTEN phosphatase. In MDCK cells, mRNA levels of the p53 target gene PTEN are induced after gamma radiation; the transfection of Snail1 prevents this up-regulation. Decreased mRNA levels of PTEN were also detected in RWP-1 cells after the ectopic expression of this transcriptional factor. Snail1 represses and associates to the PTEN promoter as detected both by the electrophoretic mobility shift assay and chromatin immunoprecipitation experiments performed with either endogenous or ectopic Snail1. The binding of Snail1 to the PTEN promoter increases after gamma radiation, correlating with the stabilization of Snail1 protein, and prevents the association of p53 to the PTEN promoter. These results stress the critical role of Snail1 in the control of apoptosis and demonstrate the regulation of PTEN phosphatase by this transcriptional repressor.
Snail1基因的产物是一种转录抑制因子，是触发上皮-间质转化所必需的。此外，Snail1在上皮细胞中的异位表达可促进细胞对凋亡的抵抗。在本研究中，我们证明Snail1引起的对γ射线诱导凋亡的抵抗与PTEN磷酸酶的抑制有关。在MDCK细胞中，γ射线照射后p53靶基因PTEN的mRNA水平升高；转染Snail1可阻止这种上调。在异位表达这种转录因子后，RWP-1细胞中也检测到PTEN的mRNA水平降低。通过电泳迁移率变动分析以及使用内源性或异位Snail1进行的染色质免疫沉淀实验均检测到，Snail1可抑制并结合到PTEN启动子上。γ射线照射后，Snail1与PTEN启动子的结合增加，这与Snail1蛋白的稳定性相关，并阻止p53与PTEN启动子的结合。这些结果强调了Snail1在细胞凋亡控制中的关键作用，并证明了这种转录抑制因子对PTEN磷酸酶的调控作用。
