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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21ES005633-02
Application #
7426429
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Reinlib, Leslie J
Project Start
2007-05-18
Project End
2010-04-30
Budget Start
2008-05-01
Budget End
2010-04-30
Support Year
2
Fiscal Year
2008
Total Cost
$192,325
Indirect Cost
Name
Upstate Medical University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
058889106
City
Syracuse
State
NY
Country
United States
Zip Code
13210
Jiang, Lingyan; Luo, Xiuquan; Shi, Jingxue et al. (2011) PDRG1, a novel tumor marker for multiple malignancies that is selectively regulated by genotoxic stress. Cancer Biol Ther 11:567-73
Shi, Jingxue; Huang, Ying; Sheikh, M Saeed (2010) Identification of Pirh2D, an Additional Novel Isoform of Pirh2 Ubiquitin Ligase. Mol Cell Pharmacol 2:21-23
Sun, Hong; Luo, Xiuquan; Montalbano, JoAnne et al. (2010) DOC45, a novel DNA damage-regulated nucleocytoplasmic ATPase that is overexpressed in multiple human malignancies. Mol Cancer Res 8:57-66
Jiang, Lingyan; Sheikh, M Saeed; Huang, Ying (2010) Decision Making by p53: Life versus Death. Mol Cell Pharmacol 2:69-77
Corcoran, Chad A; Montalbano, JoAnne; Sun, Hong et al. (2009) Identification and characterization of two novel isoforms of Pirh2 ubiquitin ligase that negatively regulate p53 independent of RING finger domains. J Biol Chem 284:21955-70
He, Qin; Shi, Jingxue; Jones, Samantha et al. (2009) Smac deficiency affects endoplasmic reticulum stress-induced apoptosis in human colon cancer cells. Mol Cell Pharmacol 1:23-28
Shi, Jingxue; He, Qin; An, Jie et al. (2009) Sulindac Sulfide Differentially Induces Apoptosis in Smac-Proficient and -Deficient Human Colon Cancer Cells. Mol Cell Pharmacol 1:92-97
Corcoran, Chad A; He, Qin; Ponnusamy, Suriyan et al. (2008) Neutral sphingomyelinase-3 is a DNA damage and nongenotoxic stress-regulated gene that is deregulated in human malignancies. Mol Cancer Res 6:795-807