Publication: Zinc deficiency induces apoptosis via mitochondrial p53- and caspase-dependent pathways in human neuronal precursor cells
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Zinc deficiency induces apoptosis via mitochondrial p53- and caspase-dependent pathways in human neuronal precursor cells

- Article in a journal -
 

Area
Metal Forming

Author(s)
Rohit Seth

Published in
Journal of Trace Elements in Medicine and Biology

Year
2014

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 24 h 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- ␮, 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.

BibTeX
@ARTICLE{
         Seth2014Zdi,
       title = "Zinc deficiency induces apoptosis via mitochondrial p53- and caspase-dependent
         pathways in human neuronal precursor cells",
       author = "Rohit Seth",
       year = "2014",
       journal = "Journal of Trace Elements in Medicine and Biology",
       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 24 h 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-
         ␮, 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.",
       ad_area = "Metal Forming"
}


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