PDRG, a novel p53 and DNA damage-regulated gene and colorectal cancer

PDRG，一种新型 p53 和 DNA 损伤调节基因与结直肠癌

• 批准号: 7265025
• 负责人: M. SAEED SHEIKH
• 金额: $ 23.5万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-18 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7265025
• 关键词: Age; Apoptosis; Cell Cycle; Cell Cycle Progression; Cells; Cellular Stress; Colorectal; Colorectal Cancer; Colorectal Neoplasms; Complex; DNA Damage; Development; Digestive System Disorders; Disease; Elderly; Event; Exhibits; Gene Expression; Genes; Genotoxic Stress; Growth; Human; Lead; Malignant Neoplasms; Mediating; Mediator of activation protein; Messenger RNA; Microtubule-Associated Proteins; Molecular; Names; Normal tissue morphology; Outcome Study; Play; Process; Protein Overexpression; Proteins; Public Health; RNA Interference; Regulation; Role; Screening procedure; Signal Transduction; Stress; System; TP53 gene; Testing; Time; Title; Toxicology; Up-Regulation; Yeasts; Zinc Fingers; base; biological adaptation to stress; environmental agent; gene interaction; improved; insight; interest; novel; response; tumor; yeast two hybrid system

DESCRIPTION (provided by applicant): Cells are constantly exposed to a variety of environmental agents some of which induce DNA damage i.e. genotoxic stress and cellular ability to effectively manage such stresses starts to decline with age. Cellular responses to DNA damage (genotoxic stress) are complex and therefore, more studies are needed to better understand the mechanisms that control such responses. We propose to characterize a novel gene, which we have named PDRG (p53 and DNA damage-regulated gene). PDRG mRNA is differentially regulated by genotoxic stress and p53 and is overexpressed in primary colorectal tumors when compared with matching normal tissues. By yeast two-hybrid screening, we have identified three important proteins including PDCD7, CIZ1 and MAP1S that exhibit interactions with PDRG. These three proteins have been involved in modulating cell cycle and/or apoptosis suggesting that PDRG may also play a role in regulating these processes. We, therefore, hypothesize that PDRG is an important mediator of cellular response to genotoxic stress and alterations in PDRG expression and PDRG-mediated signaling events are part of the mechanisms underlying the development and/or progression of digestive diseases such as colorectal cancer. Here we propose two specific aims to further characterize PDRG. Specific Aim 1 is to investigate the role of PDRG in cellular response to genotoxic stress in p53-positive and -negative cells. Specific Aim 2 is to determine the molecular basis of PDRG interactions with PDCD7, CIZ1 and MAP1S in context to genotoxic stress response. The outcome of these studies will help to determine the potential role of PDRG in digestive diseases such as colorectal malignancies and thereby further improve our understanding of the pathobiology and toxicology of human digestive diseases. Public Health Relevance Statement: A variety of environmental agents induce DNA damage i.e. genotoxic stress and cellular ability to effectively manage such stresses starts to decline with age and that is why various tumors are more common in the elderly. Here we propose to characterize a novel p53 and DNA damage-regulated gene that exhibits altered expression in human colorectal tumors. The outcome of these studies will help to determine the potential role of PDRG in diseases such as colorectal tumors and thereby further improve our understanding of the pathobiology and toxicology of human digestive diseases.

描述（由申请人提供）：细胞不断暴露于各种环境因素，其中一些会引起 DNA 损伤，即基因毒性应激，并且细胞有效管理此类应激的能力随着年龄的增长而开始下降。细胞对 DNA 损伤（基因毒性应激）的反应很复杂，因此需要更多的研究来更好地了解控制此类反应的机制。我们建议表征一个新基因，我们将其命名为 PDRG（p53 和 DNA 损伤调节基因）。 PDRG mRNA 受到基因毒性应激和 p53 的差异调节，并且与匹配的正常组织相比，在原发性结直肠肿瘤中过度表达。通过酵母二杂交筛选，我们鉴定了三种重要的蛋白质，包括PDCD7、CIZ1和MAP1S，它们与PDRG表现出相互作用。这三种蛋白参与调节细胞周期和/或细胞凋亡，表明 PDRG 也可能在调节这些过程中发挥作用。因此，我们假设 PDRG 是细胞对基因毒性应激反应的重要介质，PDRG 表达的改变和 PDRG 介导的信号事件是消化系统疾病（如结直肠癌）发生和/或进展的机制的一部分。在这里，我们提出两个具体目标来进一步表征 PDRG。具体目标 1 是研究 PDRG 在 p53 阳性和阴性细胞对基因毒性应激的细胞反应中的作用。具体目标 2 是确定 PDRG 与 PDCD7、CIZ1 和 MAP1S 在基因毒性应激反应中相互作用的分子基础。这些研究的结果将有助于确定PDRG在结直肠恶性肿瘤等消化系统疾病中的潜在作用，从而进一步提高我们对人类消化系统疾病病理学和毒理学的理解。 公共健康相关性声明：多种环境因素会引起 DNA 损伤，即基因毒性应激，并且细胞有效管理此类应激的能力开始随着年龄的增长而下降，这就是为什么各种肿瘤在老年人中更常见的原因。在这里，我们建议表征一种新的 p53 和 DNA 损伤调节基因，该基因在人类结直肠肿瘤中表现出表达改变。这些研究的结果将有助于确定PDRG在结直肠肿瘤等疾病中的潜在作用，从而进一步提高我们对人类消化系统疾病病理学和毒理学的理解。