ROLE OF ATAXIA TELANGIECTASIA IN CHECKPOINT CONTROL

放射治疗是癌症治疗的重要和有效的组成部分， 它的成功很大程度上依赖于肿瘤细胞的放射敏感性。为 肿瘤细胞的遗传组成是肿瘤发生的主要决定因素之一。 辐射抗性，了解生物化学和分子途径， 正常细胞和肿瘤细胞，决定他们是否应该DNA损伤 并在细胞周期中进展，或者它们应该经历凋亡 在开发更有效的方法来处理无线电方面至关重要- 耐药肿瘤我们研究的长期目标是确定 指定辐射诱导的DNA损伤检查点的分子途径 控制识别和操纵这些关键组件的能力 系统应允许开发更有效辐射 策略，并提供可靠的标志物，用于预测肿瘤对 放射治疗 该提案的目标是表征分子和 ATM蛋白的生化功能（共济失调毛细血管扩张突变） 及其相关蛋白质作为了解 人类细胞中的检查点控制机制。使用高度特定的 ATM抗体，我们表明，辐射诱导的激酶活性， 与ATM密切相关。我们将通过以下方法来研究其生化机制： 该辐射激活ATM激酶以及表征蛋白质， 与自动取款机一起启动检查站控制。我们有 确定了四个与ATM相关的候选蛋白质，我们提出 来研究这些相互作用的分子基础， 损伤和细胞周期控制。生化滞留分析 而ATM的分子蛋白质应该在很大程度上 定义辐射引起的DNA损伤的分子反应。

Radiation is an important and effective component of cancer therapy but its success relies largely on the radio-sensitivity of tumor cells. As the genetic composition of a tumor cell is one of the major determinants of radio-resistance, understanding the biochemical and molecular pathways in normal and tumor cells that determines whether they should the DNA damage and progress through the cell cycle or that they should undergo apoptosis is paramount in developing more effective ways to deal with radio- resistant tumors. The long-term goal of our research is to determine the molecular pathways that specify radiation-induced DNA damage checkpoint control. The ability to identify and manipulate key components of this system should allow for development of more effective radiotherapeutic strategies and provide reliable markers for predicting tumor response to radio-therapy. The goals of this proposal are to characterize the molecular and biochemical functions of the ATM protein (ataxia telangiectasia mutated) and its associated proteins as step towards understanding the molecular mechanism of a checkpoint control in human cells. Using highly specific ATM antibodies, we show that radiation induces a kinase activity that is tightly associated with ATM. We will examine the biochemical mechanism by which radiation activates ATM kinase as well as characterize proteins that act in conjunction with ATM to activate checkpoint control. We have identified four candidate proteins that associate with ATM and we propose to examine the molecular basis of these interactions as a function of DNA damage and cell cycle control. The detained analysis of the biochemical and molecular proteins of ATM should contribute in a significant way towards defining the molecular response to radiation induced DNA damage.