Department of Biotechnology, Jinan University, Guangzhou, Guangdong, China.
Division of Experimental Hematology and Cancer Biology, Children's Hospital Medical Center, Cincinnati, OH, USA.
Leukemia. 2013 Oct;27(10):2040-2046. doi: 10.1038/leu.2013.93. Epub 2013 Mar 29.
Hematopoietic stem/progenitor cells (HSPCs) function to give rise to mature blood cells. Effective DNA damage response (DDR) and maintenance of genomic stability are crucial for normal functioning of HSPCs. Mammalian target of rapamycin (mTOR) integrates signals from nutrients and growth factors to control protein synthesis, cell growth, survival and metabolism, and has been shown to regulate DDR in yeast and human cancer cells through the p53/p21 signaling cascade. Here, we show that gene targeting of mTOR in HSPCs causes a defective DDR due to a variety of DNA damage agents, mimicking that caused by deficient FANCD2, a key component of the Fanconi anemia (FA) DDR machinery. Mechanistically, mTOR(-/-) HSPCs express drastically reduced FANCD2. Consistent with these genetic findings, inactivation of mTOR in human lymphoblast cells by pp242 or Torin 1, mTOR kinase inhibitors, suppresses FANCD2 expression and causes a defective DDR that can be rescued by reconstitution of exogenous FANCD2. Further mechanistic studies show that mTOR deficiency or inactivation increases phosphorylation and nuclear translocation of nuclear factor (NF)-κB, which results in an enhanced NF-κB binding to FANCD2 promoter to suppress FANCD2 expression. Thus, mTOR regulates DDR and genomic stability in hematopoietic cells through a noncanonical pathway involving NF-κB-mediated FANCD2 expression.
造血干细胞/祖细胞（HSPCs）的功能是产生成熟的血细胞。有效的 DNA 损伤反应（DDR）和维持基因组稳定性对于 HSPCs 的正常功能至关重要。哺乳动物雷帕霉素靶蛋白（mTOR）整合来自营养物质和生长因子的信号，以控制蛋白质合成、细胞生长、存活和代谢，并且已经显示通过 p53/p21 信号级联调节酵母和人类癌细胞中的 DDR。在这里，我们表明 HSPCs 中的 mTOR 基因靶向导致各种 DNA 损伤剂引起的 DDR 缺陷，类似于关键组件范可尼贫血（FA）DDR 机制的 FANCD2 缺陷引起的 DDR。在机制上，mTOR(-/-) HSPCs 表达明显减少的 FANCD2。与这些遗传发现一致，mTOR 激酶抑制剂 pp242 或 Torin 1 对人淋巴母细胞中 mTOR 的失活抑制 FANCD2 表达并导致 DDR 缺陷，可通过重建外源 FANCD2 来挽救。进一步的机制研究表明，mTOR 缺乏或失活增加核因子 (NF)-κB 的磷酸化和核易位，导致 NF-κB 与 FANCD2 启动子结合增强，从而抑制 FANCD2 表达。因此，mTOR 通过涉及 NF-κB 介导的 FANCD2 表达的非典型途径调节造血细胞中的 DDR 和基因组稳定性。
