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首页> 外文期刊>Cell cycle >Loss of ATM positively regulates the expression of hypoxia inducible factor 1 (HIF-1) through oxidative stress: Role in the physiopathology of the disease.
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Loss of ATM positively regulates the expression of hypoxia inducible factor 1 (HIF-1) through oxidative stress: Role in the physiopathology of the disease.

机译：ATM的丧失通过氧化应激正向调节缺氧诱导因子1（HIF-1）的表达：在疾病的生理病理学中的作用。

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Ataxia Telangiectasia (AT) is an autosomal recessive disorder characterized by a wide variety of progressive clinical symptoms. This includes neuronal degeneration, oculocutaneous telangiectasias, diabetes mellitus, immunodeficiency, increased risk of cancer and sensitivity to ionizing radiation. The gene mutated in this disease, ATM (Ataxia Telangiectasia Mutated), encodes a protein kinase involved in DNA double strand breaks signalling and repair. ATM deficient cells also display an increase in oxidative stress, by poorly characterized mechanism(s), which clearly contributes to the neurodegenerative aspect of the disease. Despite these advances, the occurrence of the vascular abnormalities, glucose intolerance and insulin resistance remains poorly understood. In different cellular models where ATM expression was disrupted, we demonstrated that the absence of ATM leads to an increased expression of both subunits of the transcription factor Hypoxia Inducible Factor 1 (HIF-1). We also observed enhanced trans-activating functions of HIF-1. HIF-1 is the central regulator of responses to hypoxia which induces the transcription of genes involved in angiogenesis (e.g., VEGF-Vascular Endothelial Growth Factor) and cellular metabolism (e.g., GLUT-1). Interestingly, we demonstrated that ATM disruption positively regulates both expression and function of the basal glucose transporter GLUT-1 as well as the proangiogenic factor, VEGF. In addition, our results suggest that the absence of ATM increases HIF-1 proteins biosynthesis, and this effect is dependant on the oxidative stress existing in ATM deficient cells. Our compelling results highlight a new link between ATM deficiency and the clinical features of the disease and provide a molecular link between ATM downregulation and the increase in tumor angiogenesis observed in human breast cancers.
机译：共济失调毛细血管扩张症（AT）是一种常染色体隐性遗传疾病，其特征是各种各样的进行性临床症状。这包括神经元变性，眼皮肤毛细血管扩张，糖尿病，免疫缺陷，增加的癌症风险和对电离辐射的敏感性。在该疾病中突变的基因，ATM（共济失调毛细血管扩张症），编码参与DNA双链断裂信号传导和修复的蛋白激酶。 ATM缺陷型细胞还通过机制欠佳的机制显示出氧化应激的增加，这显然有助于疾病的神经变性。尽管取得了这些进展，但对血管异常，葡萄糖耐受不良和胰岛素抵抗的发生仍知之甚少。在ATM表达被破坏的不同细胞模型中，我们证明了ATM的缺失会导致转录因子低氧诱导因子1（HIF-1）的两个亚基的表达增加。我们还观察到了HIF-1增强的反式激活功能。 HIF-1是对缺氧反应的主要调节剂，缺氧诱导了涉及血管生成的基因（例如VEGF-血管内皮生长因子）和细胞代谢（例如GLUT-1）的转录。有趣的是，我们证明了ATM破坏正调控基础葡萄糖转运蛋白GLUT-1以及促血管生成因子VEGF的表达和功能。此外，我们的结果表明，不存在ATM会增加HIF-1蛋白的生物合成，而这种效应取决于存在于ATM缺陷细胞中的氧化应激。我们令人信服的结果突显了ATM缺乏与疾病临床特征之间的新联系，并提供了ATM下调与人类乳腺癌中观察到的肿瘤血管生成增加之间的分子联系。

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