Department of Cell Stress Biology, Roswell Park Cancer Institute; Buffalo NY, USA.
Cell Cycle. 2011 May 15;10(10):1557-62. doi: 10.4161/cc.10.10.15789.
Prolyl hydroxylases (PHDs) target hypoxia-inducible factor-1α (HIF-1α) for degradation. Hypoxia inactivates PHDs, causing accumulation of HIF-1α. In turn, HIF-1 further transactivates PHDs. It is thought that the purpose of this feedback loop is to limit HIF-1α accumulation caused by hypoxia. Here, we suggest that the feedback is intended to limit the induction of HIF-1α by insulin, growth factors, hormones, cytokines and nutrients. These stimuli induce HIF-1α by increasing its translation, not by inhibiting PHDs. As exemplified herein, in a mTOR-dependent manner, insulin transiently induced HIF-1α in retinal pigment epithelial (RPE) cells. Induction of HIF-1α was followed by activation of HIF-dependent transcription. Furthermore, DFX, which inactivates PHDs, potentiated the induction of HIF-1α by insulin. We propose that the most relevant function of the PHD-HIF feedback loop is to limit the induction of HIF-1α by mTOR. The failure to limit mTOR-dependent induction of HIF-1 may contribute to age-related macular degeneration and diabetic retinopathy, suggesting rapamycin for prevention of these age-related diseases.
脯氨酰羟化酶（PHD）靶向缺氧诱导因子-1α（HIF-1α）进行降解。缺氧使 PHD 失活，导致 HIF-1α 积累。反过来，HIF-1 进一步反式激活 PHD。人们认为这种反馈循环的目的是限制缺氧引起的 HIF-1α 积累。在这里，我们建议该反馈旨在限制胰岛素、生长因子、激素、细胞因子和营养物质对 HIF-1α 的诱导。这些刺激通过增加其翻译而不是抑制 PHD 来诱导 HIF-1α。正如本文所示，以 mTOR 依赖的方式，胰岛素在视网膜色素上皮（RPE）细胞中短暂诱导 HIF-1α。HIF-1α 的诱导伴随着 HIF 依赖性转录的激活。此外，DFX 使 PHD 失活，增强了胰岛素诱导 HIF-1α 的作用。我们提出，PHD-HIF 反馈循环的最相关功能是限制 mTOR 对 HIF-1α 的诱导。未能限制 mTOR 依赖性 HIF-1α 的诱导可能导致年龄相关性黄斑变性和糖尿病性视网膜病变，这表明雷帕霉素可用于预防这些与年龄相关的疾病。
