Molecular Analysis Of Cell Cycle Control During Carcinogenesis

致癌过程中细胞周期控制的分子分析

• 批准号: 8148980
• 负责人: Richard Paules
• 金额: $ 101.73万
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8148980
• 关键词: Cell Cycle Regulation; Molecular Analysis; carcinogenesis

The overall goal of the research of the group is to provide a better understanding of the regulatory networks that control critical cellular responses to environmental stresses. We are currently investigating cell cycle checkpoint responses to cellular damage from various environmental stresses and how defects in these responses can contribute to cancer. Intricate regulatory networks control stress-induced cell cycle checkpoints and these networks respond in a damage- and cell type-specific manner. Group members are presently studying the critical molecular events that regulate cell cycle checkpoint signaling following exposures to ionizing radiation (IR), ultraviolet (UV) radiation, oxidative stress and other environmental stresses. In addition, we are investigating the cellular specificity of these processes in normal human cells (e.g. diploid fibroblasts and normal breast epithelial cells) and cells with genetic alterations in cancer susceptibility genes, such as the gene mutated in ataxia telangiectasia (ATM). Three independent isogenic lines of normal and ATM-deficient breast epithelial cells have been established through stable shRNA knock-down techniques in order to obtain populations of mammary epithelial cells that differ only in their levels of ATM. Studies of DNA damage signaling in these cells has provided novel mechanistic insight into the function of the ATM, the related ATR protein kinase and the DNA-dependent protein kinase (DNA-PK) in the G2 checkpoint response to ionizing radiation induced cellular damage. In studies performed in collaboration with Barry Sleckman and colleagues, we have investigated the gene expression responses and signaling pathways activated by genotoxic radiation-induced DNA damage in mouse pre-B cells that are from mouse strains that are deficient in various DNA damage response and repair genes. We have been able to show that in addition to the expected cell cycle checkpoint and DNA damage and repair responses, these double strand breaks also initiate, in part, an overlapping lymphocyte-specific genetic program that contributes to B-cell development and differentiation, as we had previously found following physiological Rag-mediated double strand breaks.

该小组研究的总体目标是更好地了解控制对环境压力的关键细胞反应的调控网络。我们目前正在研究细胞周期检查点对各种环境压力造成的细胞损伤的反应，以及这些反应中的缺陷如何导致癌症。复杂的调控网络控制应激诱导的细胞周期检查点，这些网络以损伤和细胞类型特异性的方式响应。小组成员目前正在研究电离辐射（IR）、紫外线（UV）辐射、氧化应激和其他环境应激暴露后调节细胞周期检查点信号传导的关键分子事件。此外，我们正在研究这些过程在正常人类细胞（例如二倍体成纤维细胞和正常乳腺上皮细胞）和癌症易感基因发生遗传改变的细胞中的细胞特异性，例如共济失调毛细血管扩张症（ATM）中的基因突变。三个独立的正常和ATM缺陷型乳腺上皮细胞的等基因系已经通过稳定的shRNA敲低技术建立，以获得乳腺上皮细胞的群体，不同的只是在他们的ATM水平。对这些细胞中DNA损伤信号的研究为ATM、相关ATR蛋白激酶和DNA依赖性蛋白激酶（DNA-PK）在G2检查点对电离辐射诱导的细胞损伤的反应中的功能提供了新的机制见解。 在与巴里Sleckman及其同事合作进行的研究中，我们研究了基因表达反应和信号通路激活的遗传毒性辐射诱导的DNA损伤的小鼠前B细胞，是从小鼠品系，缺乏各种DNA损伤反应和修复基因。 我们已经能够表明，除了预期的细胞周期检查点和DNA损伤和修复反应，这些双链断裂也启动，部分，重叠淋巴细胞特异性遗传程序，有助于B细胞的发育和分化，因为我们以前发现以下生理Rag介导的双链断裂。