title: Zinc deficiency induces apoptosis via mitochondrial p53- and caspase-dependent pathways in human neuronal precursor cells.
abstract: Previous studies have shown that zinc deficiency leads to apoptosis of neuronal precursor cells in vivo and in vitro. In addition to the role of p53 as a nuclear transcription factor in zinc deficient cultured human neuronal precursors (NT-2), we have now identified the translocation of phosphorylated p53 to the mitochondria and p53-dependent increases in the pro-apoptotic mitochondrial protein BAX leading to a loss of mitochondrial membrane potential as demonstrated by a 25% decrease in JC-1 red:green fluorescence ratio. Disruption of mitochondrial membrane integrity was accompanied by efflux of the apoptosis inducing factor (AIF) from the mitochondria and translocation to the nucleus with a significant increase in reactive oxygen species (ROS) after 24h of zinc deficiency. Measurement of caspase cleavage, mRNA, and treatment with caspase inhibitors revealed the involvement of caspases 2, 3, 6, and 7 in zinc deficiency-mediated apoptosis. Down-stream targets of caspase activation, including the nuclear structure protein lamin and polyADP ribose polymerase (PARP), which participates in DNA repair, were also cleaved. Transfection with a dominant-negative p53 construct and use of the p53 inhibitor, pifithrin-μ, established that these alterations were largely dependent on p53. Together these data identify a cascade of events involving mitochondrial p53 as well as p53-dependent caspase-mediated mechanisms leading to apoptosis during zinc deficiency.
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL, USA.
authors.forename: Rohit
authors.initials: R
authors.lastname: Seth
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL, USA; Program in Neuroscience, Florida State University, Tallahassee, FL, USA.
authors.forename: Rikki S
authors.initials: RS
authors.lastname: Corniola
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL, USA.
authors.forename: Shannon D
authors.initials: SD
authors.lastname: Gower-Winter
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Morgan
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Bishop
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL, USA; Program in Neuroscience, Florida State University, Tallahassee, FL, USA. Electronic address: cathy.levenson@med.fsu.edu.
authors.forename: Cathy W
authors.initials: CW
authors.lastname: Levenson
mesh_terms: D017209:Apoptosis; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D034882:Lamins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D058953:Neural Stem Cells / Q000378:metabolism*; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D021381:Protein Transport; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015032:Zinc / Q000172:deficiency*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D051033:Apoptosis Inducing Factor; D034882:Lamins; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; D015032:Zinc
keywords: Apoptosis; Caspase; NT-2; Zinc; p53