Nucleolar signaling in cancer

项目总结/摘要 核仁是一种细胞器，进行核糖体的合成，并具有多种感觉功能。 和调节功能。干扰核仁中的生物合成过程会触发p53- 一种依赖性核仁应激反应，在某些情况下促进细胞死亡，但在某些情况下可以是细胞保护性的。 其他的，导致细胞对基因毒性药物的抗性增加。核仁的调节功能是 这对于理解肿瘤对化疗药物的反应很重要，但是核仁压力 影响治疗结果的因素尚不清楚。我们最近的研究表明，核仁应力可能会交叉- 激活DNA损伤反应（DDR）途径的成分，有助于维持基因组的完整性。 我们假设，核仁参与DDR机制的能力对于及时的 激活细胞生存所必需的细胞防御机制。本提案重点关注信令链路 在核仁和ATM蛋白激酶之间，ATM蛋白激酶是DDR的关键介质。使用我们以前的 开发细胞模型的特定核糖体生物合成步骤的条件抑制，我们将确定 ATM在核仁应激中的激活与其激活的方式是否相似或不同 DNA损伤和氧化应激。我们还将检查与应激相关的染色质标记物 核仁及其与ATM复合物的可能共定位。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。 反应本研究将进一步加深我们对核仁应激诱导的信号转导机制的理解。 所产生的知识将是重要的，因为它可以应用于增加药物的差异边际。 在正常和肿瘤细胞中的敏感性，从而提高癌症治疗干预的功效 患者

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.