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. ? ? ?
