Friedrich Miescher Institute for Biomedical Research, Maulbeerstrase, Basel, Switzerland.
Cell Cycle. 2010 Oct 1;9(19):3933-44. doi: 10.4161/cc.9.19.13154. Epub 2010 Oct 26.
Oct1 is a ubiquitously expressed transcription factor that is induced in response to DNA damage to modulate gene expression. Herein, Oct1 deficient mouse embryonic fibroblasts were used as a model to study the importance of Oct1 in cellular stress response. Cells lacking Oct1 kept proliferating and bypassed the G(1) cell cycle arrest induced by glucose or amino acid starvation. Indeed, mTOR-mediated regulation of proliferation was abolished in Oct1(-/-) cells starved for glucose or amino acids and Oct1(-/-) cells were also insensitive to mTOR inhibition by rapamycin. Furthermore, in wild-type cells, Oct1 controls the transcription of the CDK inhibitor p27(Kip1) downstream of the mTOR pathway and Oct1-null cells failed to upregulate p27(Kip1) in response to rapamycin or glucose starvation. p27(Kip1) is required for rapamycin or nutrient starvation-induced G(1)-arrest, as p27(-/-) fibroblasts were largely insensitive to rapamycin treatment or glucose starvation. Thus, Oct1 appears to be a critical mediator of the growth arrest induced by mTOR inhibition via the control of p27(Kip1) expression.
Oct1 是一种广泛表达的转录因子，它在受到 DNA 损伤后被诱导，以调节基因表达。在此，使用缺乏 Oct1 的小鼠胚胎成纤维细胞作为模型，研究 Oct1 在细胞应激反应中的重要性。缺乏 Oct1 的细胞继续增殖，并绕过葡萄糖或氨基酸饥饿引起的 G1 细胞周期阻滞。事实上，在缺乏葡萄糖或氨基酸的 Oct1(-/-)细胞中，mTOR 介导的增殖调控被废除，并且 Oct1(-/-)细胞对 rapamycin 抑制 mTOR 也不敏感。此外，在野生型细胞中，Oct1 控制着 mTOR 通路下游 CDK 抑制剂 p27(Kip1)的转录，而 Oct1 缺失细胞在 rapamycin 或葡萄糖饥饿时未能上调 p27(Kip1)。p27(Kip1)是 rapamycin 或营养饥饿诱导的 G1 期阻滞所必需的，因为 p27(-/-)成纤维细胞对 rapamycin 处理或葡萄糖饥饿的敏感性大大降低。因此，Oct1 似乎是通过控制 p27(Kip1)表达，介导 mTOR 抑制诱导的生长阻滞的关键介质。
