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http://dx.doi.org/10.14348/molcells.2015.2142

Poly(ADP-ribosyl)ation of p53 Contributes to TPEN-Induced Neuronal Apoptosis  

Kim, Hyun-Lim (Department of Molecular Biology, Sejong University)
Ra, Hana (Department of Molecular Biology, Sejong University)
Kim, Ki-Ryeong (Department of Molecular Biology, Sejong University)
Lee, Jeong-Min (Department of Molecular Biology, Sejong University)
Im, Hana (Department of Molecular Biology, Sejong University)
Kim, Yang-Hee (Department of Molecular Biology, Sejong University)
Abstract
Depletion of intracellular zinc by N,N,N,N-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN) induces p53-mediated protein synthesis-dependent apoptosis of mouse cortical neurons. Here, we examined the requirement for poly(ADP-ribose) polymerase (PARP)-1 as an upstream regulator of p53 in zinc depletion-induced neuronal apoptosis. First, we found that chemical inhibition or genetic deletion of PARP-1 markedly attenuated TPEN-induced apoptosis of cultured mouse cortical neurons. Poly(ADP-ribosyl)ation of p53 occurred starting 1 h after TPEN treatment. Suggesting the critical role of PARP-1, the TPEN-induced increase of stability and activity of p53 as well as poly(ADP-ribosyl)ation of p53 was almost completely blocked by PARP inhibition. Consistent with this, the induction of downstream pro-apoptotic proteins PUMA and NOXA was noticeably reduced by chemical inhibitors or genetic deletion of PARP-1. TPEN-induced cytochrome C release into the cytosol and caspase-3 activation were also blocked by inhibition of PARP-1. Taken together, these findings indicate that PARP-1 is essential for TPEN-induced neuronal apoptosis.
Keywords
caspase-3; NOXA; p53; poly(ADP-ribose) polymerase; PUMA;
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