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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

基本信息

批准号：
7426429
负责人：
M. SAEED SHEIKH
金额：
$ 19.23万
依托单位：
UPSTATE MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-18 至 2010-04-30
项目状态：
已结题

项目摘要

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(申请人提供)：细胞不断地暴露在各种环境因素中，其中一些会导致DNA损伤，即遗传毒性压力，细胞有效应对这种压力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)的反应是复杂的，因此，需要更多的研究来更好地了解控制这种反应的机制。我们提出了一个新的基因，我们将其命名为PDRG(P53和DNA损伤调节基因)。PDRG mRNA受基因毒性应激和P53的差异调节，与匹配的正常组织相比，在原发结直肠肿瘤中高表达。通过酵母双杂交筛选，我们发现了与PDRG相互作用的三个重要蛋白：PDCD7、CIZ1和MAP1S。这三种蛋白参与了细胞周期和/或细胞凋亡的调节，提示PDRG也可能在调节这些过程中发挥作用。因此，我们假设PDRG是细胞对遗传毒性应激反应的重要介质，PDRG表达的改变和PDRG介导的信号事件是导致消化系统疾病(如结直肠癌)发生和/或进展的部分机制。在这里，我们提出了两个具体的目标，以进一步描述PDRG。具体目的1是研究PDRG在P53阳性和阴性细胞对遗传毒性应激的细胞反应中的作用。具体目的2是确定PDRG与PDCD7、CIZ1和MAP1S在遗传毒性应激反应背景下相互作用的分子基础。这些研究的结果将有助于确定PDRG在结直肠癌等消化系统疾病中的潜在作用，从而进一步加深我们对人类消化系统疾病的病理生物学和毒理学的了解。公共卫生相关声明：各种环境因素会导致DNA损伤，即遗传毒性应激，细胞有效应对这种应激的能力随着年龄的增长而开始下降，这就是为什么各种肿瘤在老年人中更常见的原因。在这里，我们建议描述一个新的p53和DNA损伤调节基因，它在人类结直肠肿瘤中表现出变化的表达。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，从而进一步加深我们对人类消化系统疾病的病理生物学和毒理学的了解。