The role of p53 tumor-suppressor protein is most well known for it role in preventing cancer based on its ability to transcriptionally activate effector proteins that cause cell cycle arrest in G1 that allows time for repair of DNA damage, or apoptosis which eliminates cells with damaged genomes. Loss of p53 activity by mutation is a major predisposing factor to transformation. While the effects of p53 in the cancer field are well known, its influence upon neurodegenerative processes and diseases are less recognized but are likely to be very influential in neuronal stress and injury. The cellular decision for growth control or apoptosis has been shown in our laboratory to be greatly influenced by cell signaling events such as phosphorylation at specific sites on p53. We believe posttranslational events such as phosphorylation and acetylation alter p53 conformation and affect p53?s promoter selectivity and affinity for coactivator or corepressor complexes that ultimately determine effector protein transactivation and p53 protein interactions to decide cell fate. Previous work in this our has studied effects of stressors like ionizing radiation and reactive oxygen species (ROS) in wt p53 expressing tumor cells. A primary feature of this work was the use of tumor cells or immortalized cells which contained wt p53 gene but nevertheless, were actively proliferating during the course of experiments. Our laboratory is now studying neuronal cell models (AF5 and PC12 cells) of cell death by ROS using hydrogen peroxide and nitric oxide. These studies are being conducted in both proliferating and differentiated cell states to test the hypothesis that the differing gene expression states of cycling and diffenentiated cells influence their survival and apoptotic response to ROS agents. Our results suggest that this is apoptosis, p53 phosphorylation and p53-dependent effector gene expression changes when cells are engaged in cell division compared to Go growth arrest. We have been studying peripheral and central nervous system derived cell lines that serve as in vitro models of neuronal response. Our group has been collaborating with Dr. Freed at NIDA/NIH in Baltimore in using some of their recently formed neuronal cell lines to test this hypothesis. The intent of such studies is to determine differences in wt p53 gene expression in various neuronal cells in response to apoptotic reagents to determine possible roles in neurodegeneration and cell death. Results of these studies will be published and presented at the Society of Neurobiology annual meetings.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES023012-11
Application #
7168257
Study Section
(NCT)
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
2005
Total Cost
Indirect Cost
Name
U.S. National Inst of Environ Hlth Scis
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Brynczka, Christopher; Merrick, B Alex (2008) The p53 transcriptional target gene wnt7b contributes to NGF-inducible neurite outgrowth in neuronal PC12 cells. Differentiation 76:795-808
Brynczka, Christopher; Labhart, Paul; Merrick, B Alex (2007) NGF-mediated transcriptional targets of p53 in PC12 neuronal differentiation. BMC Genomics 8:139
Brynczka, Christopher; Merrick, Bruce Alex (2007) Nerve growth factor potentiates p53 DNA binding but inhibits nitric oxide-induced apoptosis in neuronal PC12 cells. Neurochem Res 32:1573-85
McNeill-Blue, Charlesene; Wetmore, Barbara A; Sanchez, Joseph F et al. (2006) Apoptosis mediated by p53 in rat neural AF5 cells following treatment with hydrogen peroxide and staurosporine. Brain Res 1112:1-15
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Zhao, W; He, C; Rotter, V et al. (1999) An intragenic deletion of nuclear localization signal-1 of p53 tumor suppressor gene results in loss of apoptosis in murine fibroblasts. Cancer Lett 147:101-8