Control of lymphomagenesis by ATM through ROS, mTOR and PP2A signaling

描述（由申请人提供）：共济失调毛细血管扩张症（a - t）是一种人类常染色体隐性遗传病，部分特征为淋巴肿瘤发生。a - t是由Atm基因内的突变引起的，导致基因产物Atm的功能丧失。最近的研究表明，Atm失活也与非a - t患者的散发性淋巴样肿瘤有关。因此，研究ATM在抑制淋巴细胞肿瘤发生中的作用，对淋巴细胞肿瘤的化学预防具有重要意义。ATM是一种丝氨酸/苏氨酸激酶，调节DNA损伤修复所需的各种反应。ATM通过自磷酸化被激活，随后启动对细胞周期调节重要的多种底物的磷酸化。特别是，我们实验室的工作主要集中在ATM在调节未成熟胸腺细胞增殖和分化中的作用，以及使用ATM敲除细胞系和小鼠通过糖皮质激素和抗氧化剂预防胸腺淋巴瘤的发展。我们目前的研究结果表明，在没有ATM的情况下，DNA合成和c-Myc水平增加，哺乳动物雷帕霉素靶蛋白（mTOR）下游分子4E-BPI的磷酸化增加，表明ATM可能通过mTOR信号通路调节胸腺细胞发育。此外，最近的证据表明，ATM可能通过mTOR途径或通过改变活性氧（ROS）水平激活PP2A，这是一种已知的肿瘤抑制因子。因此，我们假设ATM通过调节细胞周期相关分子和致癌转录调节因子来阻止胸腺细胞发育过程中的淋巴瘤发生。我们认为这种调控是通过mTOR和/或PP2A信号通路直接或通过硫醇氧化还原机制发生的。为了验证这一假设，我们将通过检测ATM激酶靶向分子和ATM -/-胸腺细胞中的蛋白水平来确定ATM在控制mTOR信号通路中的作用。我们还将通过平衡胸腺细胞的氧化还原状态和监测蛋白质水平和活性，确定ATM在调节PP2A活性中的直接或间接作用。这项研究应用的基本原理是胸腺细胞发育中atm靶向分子的鉴定将使我们能够从药理学上调节它们的活性。这些研究将显著推进我们的长期目标，了解ATM如何调节淋巴细胞发育，ATM如何防止淋巴细胞肿瘤发生，并最终找到治疗或预防由ATM失活引起的淋巴细胞肿瘤的方法。

DESCRIPTION (provided by applicant): Ataxia telangiectasia (A-T) is a human autosomal recessive disease characterized in part by lymphoid tumorigenesis. A-T is caused by mutations within the Atm gene, resulting in a loss of function of the gene product, ATM. Recent studies have shown that inactivation of Atm is also associated with sporadic lymphoid tumors in non-A-T patients. Therefore, it is of broad significance for lymphoid tumor chemoprevention to study the role of ATM in suppressing lymphoid tumorigenesis. ATM is a serine/threonine kinase that regulates a variety of responses required for DNA damage repair. ATM becomes activated via autophosphorylation and subsequently initiates phosphorylation of multiple substrates important for cell cycle regulation. In particular, work in our laboratory has focused on the role of ATM in regulation of immature thymocyte proliferation and differentiation, and on prevention of thymic lymphoma development by glucocorticoids and antioxidants using Atm knockout cell lines and mice. Our current findings demonstrate that in the absence of ATM, DNA synthesis and c-Myc levels are increased and phosphorylation of 4E-BPI, a downstream molecule of mammalian target of rapamycin (mTOR), is increased, suggesting that ATM may regulate thymocyte development through the mTOR signaling pathway. In addition, recent evidence suggests that ATM may activate PP2A, a known tumor suppressor, either through the mTOR pathway or by changing reactive oxygen species (ROS) levels. We therefore hypothesize that ATM prevents lymphomagenesis during thymocyte development by regulating cell cycle related molecules and oncogenic transcriptional regulators. We propose that this regulation occurs through the mTOR and/or PP2A signaling pathways, either directly or through thiol redox mechanisms. To test this hypothesis we will identify the role of ATM in controlling mTOR signaling pathways by examining ATM kinase targeted molecules and protein levels in Atm-/- thymocytes. We will also identify the role of ATM in regulating PP2A activity as being direct or indirect, through balancing the redox state in thymocytes and monitoring protein levels and activities. The rationale for this research application is that identification of ATM-targeted molecules in thymocyte development will allow us to regulate their activities pharmacologically. These studies will significantly advance us towards our long-term goal of understanding how ATM regulates lymphocyte development, how ATM prevents lympoid tumorigenesis, and ultimately finding ways to treat or prevent lymphoid tumors caused by Atm inactivation.