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Nuclear and mitochondrial functions of p53 in zinc deficient human neuronal precursor cells
Author(s) -
Corniola Rikki S,
Levenson Cathy W
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.922.8
Subject(s) - biology , mitochondrion , programmed cell death , microbiology and biotechnology , apoptosis , cell cycle , cell growth , biochemistry
Our previous work has shown a role for zinc and the tumor suppressor protein p53 in the regulation of neuronal precursor cell proliferation and survival in vivo and in vitro. In human neuronal precursor cells (NT‐2) zinc deficiency results in increased p53 nuclear abundance, where it acts as a DNA‐binding transcription factor to regulate 14 downstream target genes, including cell cycle arrest genes (eg 1.8‐fold up‐regulation of reprimo mRNA) and a number of pro‐apoptotic genes including transforming growth factor‐β (+1.4‐fold) and retinoblastoma‐1 (+4.5‐fold) leading to decreases in BrdU labeling and increases in cell death. A dominant‐negative p53 gene construct confirmed the p53‐dependent nature of this regulation during zinc deficiency. In addition to the nuclear translocation of p53, we have also shown that p53 translocates to the mitochondria where it plays a role in the generation of mitochondrial reactive oxygen species (ROS) as measured by dihydrorhodamine fluorescence. Pre‐treatment with pifithrin‐α, a p53 inhibitor, prevents the generation of ROS. Additionally, there is 50% decrease in total superoxide dismutase activity (p<0.05), and a 2‐fold increase in glutathione peroxidase mRNA. These data identify a role for zinc in the nuclear and mitochondrial mechanisms that control neuronal stem cell proliferation and survival. Supported by Susan E. Lucas Fellowship in the Neurosciences. Grant Funding Source Phoenix Foundation