Medway School of Pharmacy, University of Kent, Anson Building, Central Avenue, Chatham Maritime, Kent, ME4 4TB, UK.
Cell Mol Life Sci. 2014 Feb;71(4):699-710. doi: 10.1007/s00018-013-1421-2. Epub 2013 Jul 20.
Mammalian myeloid cells are crucial effectors of host innate immune defense. Normal and pathological responses of these cells require adaptation to signaling stress through the hypoxia-inducible factor 1 (HIF-1) transcription complex. Adapted cells activate the mammalian target of rapamycin (mTOR), via S2448 phosphorylation, which induces de novo translation of vital signaling proteins. However, the molecular mechanisms underlying this signaling dogma remain unclear. Here, we demonstrate for the first time that inactivation of HIF-1, by silencing its inducible alpha subunit, significantly decreases mTOR S2448 phosphorylation caused by ligand-dependent activation of human myeloid leukemia cells. This shows that HIF-1 is essential for the activation of mTOR and serves at a crucial juncture of myeloid cell function in both in vitro and in vivo systems.
哺乳动物髓系细胞是宿主固有免疫防御的关键效应细胞。这些细胞的正常和病理反应需要通过缺氧诱导因子 1（HIF-1）转录复合物适应信号应激。适应的细胞通过 S2448 磷酸化激活雷帕霉素靶蛋白（mTOR），从而诱导重要信号蛋白的从头翻译。然而，这一信号教条的分子机制仍不清楚。在这里，我们首次证明，通过沉默其诱导型α亚基使 HIF-1失活，可显著降低人髓系白血病细胞配体依赖性激活引起的 mTOR S2448 磷酸化。这表明 HIF-1对于 mTOR 的激活是必不可少的，并在体外和体内系统中作为髓系细胞功能的关键环节发挥作用。
