Nucleolar signaling in cancer

项目摘要/摘要 核仁是进行核糖体合成的细胞器，具有多种感觉。 以及细胞内的调节功能。干扰核仁中的生物合成过程会触发P53- 依赖性核仁应激反应，在某些情况下促进细胞死亡，但在某些情况下可起细胞保护作用 其他的，导致细胞对遗传毒性药物的抗药性增加。核仁的调节功能是 因此对于了解肿瘤对化疗药物的反应很重要，但核仁应激到底是如何 对治疗结果的影响尚不清楚。我们最近的研究表明，核仁应激可能交叉- 激活有助于维持基因组完整性的DNA损伤反应(DDR)途径的组件。 我们假设，核仁参与DDR机制的能力对于及时 激活对细胞生存至关重要的细胞防御机制。本提案的重点是信令链路 在核仁和ATM蛋白激酶之间，ATM蛋白激酶是DDR的关键中介。使用我们以前的 开发了有条件地抑制特定核糖体生物合成步骤的细胞模型，我们将确定 核仁应激过程中ATM的激活与其激活的方式是相似还是不同 由DNA损伤和氧化应激引起。我们还将检查与应激相关的染色质标记 核仁及其与ATM复合体的可能共定位。最后，分析转录组的变化 ATM熟练和缺陷细胞将被用来评估ATM在核仁应激中的生物学作用 回应。这项研究将促进我们对核仁应激诱导的信号机制的理解。 产生的知识将是重要的，因为它可以被应用于增加药物的差别边际 正常细胞和肿瘤细胞的敏感性，从而提高癌症治疗干预的有效性 病人。

Project Summary/Abstract The nucleolus is a cellular organelle that carries out the synthesis of ribosomes and has a multitude of sensory and regulatory functions in the cell. Interference with biosynthetic processes in the nucleolus triggers a p53- dependent nucleolar stress response that promotes cell death in some contexts but can be cytoprotective in others, leading to increased cell resistance to genotoxic drugs. The regulatory functions of the nucleolus are thus important for understanding tumor responses to chemotherapy agents, but how exactly nucleolar stress influences therapeutic outcomes is not known. Our recent studies suggest that nucleolar stress may cross- activate components of the DNA damage response (DDR) pathway that helps to maintain genome integrity. We hypothesize that the capacity of the nucleolus to engage the DDR machinery is important for the timely activation of cellular defense mechanisms essential for cell survival. This proposal focuses on the signaling link between the nucleolus and the ATM protein kinase, a key mediator of the DDR. Using our previously developed cell models for the conditional inhibition of specific ribosome biosynthesis steps, we will determine whether ATM activation during nucleolar stress occurs in a similar or different way compared with its activation by DNA damage and oxidative stress. We will also examine chromatin markers associated with the stressed nucleolus and their possible colocalization with ATM complexes. Finally, profiling transcriptome changes in ATM-proficient and deficient cells will be used to assess the biological role of ATM in the nucleolar stress response. This study will advance our understanding of the signaling mechanisms induced by nucleolar stress. The generated knowledge will be important as it can be applied to increase the differential margins of drug sensitivity in normal and tumor cells and thus improve the efficacy of therapeutic interventions in cancer patients.