Mireuta Matei, Darnel Andrew, Pollak Michael
Departments of Medicine and Oncology, Lady Davis Institute for Medical Research, Montreal SMBD Jewish General Hospital, and McGill University, Montreal, Quebec, CanadaH3T 1E2.
Growth Factors. 2010 Aug;28(4):243-55. doi: 10.3109/08977191003745472.
Insulin-like growth factor binding protein 2 (IGFBP-2) has been implicated in the pathophysiology of neoplasia. The PI3K/AKT/mTOR pathway has recently been shown to be a predominant regulator of IGFBP-2 at the protein level in MCF-7 breast cancer cells. However, there are gaps in knowledge with respect to the molecular mechanisms that underlie this regulation. Here, we show that the PI3K/AKT/mTOR pathway regulates IGFBP-2 protein levels by modulating IGFBP-2 mRNA abundance in MCF-7 cells. This change is achieved by regulating transcription through a critical region present in the first 200 bp upstream of the transcription initiation site where Sp1 transcription factor binds and drives transcription. IGF-1 treatment leads to increased nuclear abundance of Sp1 and increased IGFBP-2 mRNA and protein levels. Rapamycin and LY294002 induce a decline in Sp1 nuclear abundance and IGFBP-2 mRNA and protein levels. This work provides a mechanistic explanation for the observed effects of the PI3K/AKT/mTOR pathway on IGFBP-2 levels in MCF-7 cells.
胰岛素样生长因子结合蛋白2（IGFBP - 2）与肿瘤形成的病理生理学有关。最近研究表明，PI3K/AKT/mTOR信号通路是MCF - 7乳腺癌细胞中IGFBP - 2蛋白水平的主要调节因子。然而，关于这种调节作用的分子机制仍存在知识空白。在此，我们发现PI3K/AKT/mTOR信号通路通过调节MCF - 7细胞中IGFBP - 2 mRNA丰度来调控IGFBP - 2蛋白水平。这种变化是通过位于转录起始位点上游200 bp内的关键区域调节转录实现的，该区域是Sp1转录因子结合并驱动转录的位点。IGF - 1处理导致Sp1在细胞核中的丰度增加，同时IGFBP - 2 mRNA和蛋白水平升高。雷帕霉素和LY294002可导致Sp1细胞核丰度下降以及IGFBP - 2 mRNA和蛋白水平降低。这项研究为PI3K/AKT/mTOR信号通路对MCF - 7细胞中IGFBP - 2水平的影响提供了机制解释。
