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

描述（由申请人提供）：细胞不断暴露于各种环境因子中，其中一些诱发DNA损伤，即基因毒性应激，细胞有效管理这种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。我们建议描述一个新的基因，我们已经命名为PDRG （p53和DNA损伤调节基因）。PDRG mRNA受基因毒性应激和p53的差异调控，与匹配的正常组织相比，PDRG mRNA在原发性结直肠肿瘤中过表达。通过酵母双杂交筛选，我们发现了PDCD7、CIZ1和MAP1S这3种与PDRG相互作用的重要蛋白。这三种蛋白参与调节细胞周期和/或凋亡，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介导的信号事件是结肠直肠癌等消化系统疾病发生和/或进展的潜在机制的一部分。在这里，我们提出了两个具体的目标，以进一步表征PDRG。特异性目的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。特异性目的2是确定基因毒性应激反应中PDRG与PDCD7、CIZ1和MAP1S相互作用的分子基础。这些研究的结果将有助于确定PDRG在消化道疾病如结肠直肠恶性肿瘤中的潜在作用，从而进一步提高我们对人类消化道疾病的病理生物学和毒理学的认识。

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.