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首页> 外文期刊>Cell cycle >Oxygen sensing is impaired in ATM-defective cells.
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Oxygen sensing is impaired in ATM-defective cells.

机译：ATM缺陷细胞中的氧气感应受损。

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The transcription factor hypoxia-inducible factor 1alpha (HIF-1alpha) is a master regulator of cell adaptation to decreasing oxygen levels. High oxygen tension promotes proteosomal degradation of HIF-1alpha via a pathway that requires hydroxylation of prolines 402 and 564. Low oxygen tension, hypoxia, inactivates the hydroxylases responsible for these modifications through a mechanism that is not fully understood but appears to require mitochondrial respiration and production of reactive oxygen species, ROS. Cells from individuals affected by ataxia telangiectasia syndrome have an impaired mitochondrial activity and a constitutive oxidative stress. Here we show that, in these cells, HIF-1alpha is efficiently degraded even in condition of low oxygen tension. Mechanistically this depends from a blunted increase in intracellular concentration of ROS in response to hypoxia which in turn is due to an increased cellular capacity of buffering ROS. We suggest that regulation of HIF-1alpha stability may depend on fold change of ROS relative to the basal level more than on their absolute value. Since elevated oxidative stress is a hallmark of many human disorders our finding may be relevant to different pathologies.
机译：转录因子缺氧诱导因子1alpha（HIF-1alpha）是细胞适应氧含量降低的主要调节因子。高氧张力通过需要脯氨酸402和564羟化的途径促进HIF-1alpha的蛋白体降解。低氧张力，低氧会通过一种尚不完全了解但似乎需要线粒体呼吸作用和机制来失活负责这些修饰的羟化酶。生产活性氧，ROS。受共济失调性毛细血管扩张综合征影响的个体的细胞线粒体活性受损，并构成氧化应激。在这里我们表明，在这些细胞中，即使在低氧张力下，HIF-1α也会被有效降解。从机械上讲，这取决于对缺氧的反应中ROS细胞内浓度的平缓增加，这又是由于缓冲ROS的细胞容量增加所致。我们建议，HIF-1alpha稳定性的调节可能更多地取决于相对于基础水平的ROS的倍数变化，而不是其绝对值。由于升高的氧化应激是许多人类疾病的标志，因此我们的发现可能与不同的病理学有关。

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