title: Poly(ADP-ribosyl)ation of p53 contributes to TPEN-induced neuronal apoptosis.
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 proapoptotic 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.
authors: Department of Molecular Biology, Sejong University, Seoul 143-747, Korea.
authors: Hyun-Lim
authors: HL
authors: Kim
authors: Department of Molecular Biology, Sejong University, Seoul 143-747, Korea.
authors: Hana
authors: H
authors: Ra
authors: Department of Molecular Biology, Sejong University, Seoul 143-747, Korea.
authors: Ki-Ryeong
authors: KR
authors: Kim
authors: Department of Molecular Biology, Sejong University, Seoul 143-747, Korea.
authors: Jeong-Min
authors: JM
authors: Lee
authors: Department of Molecular Biology, Sejong University, Seoul 143-747, Korea.
authors: Hana
authors: H
authors: Im
authors: Department of Molecular Biology, Sejong University, Seoul 143-747, Korea.
authors: Yang-Hee
authors: YH
authors: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D005029:Ethylenediamines / Q000494:pharmacology*; D007150:Immunohistochemistry; D051379:Mice; D018613:Microscopy, Confocal; D009474:Neurons / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015032:Zinc / Q000172:deficiency / Q000378:metabolism*
chemical_list: D005029:Ethylenediamines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D016159:Tumor Suppressor Protein p53; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D015032:Zinc; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine
keywords: NOXA; PUMA; caspase-3; p53; poly(ADP-ribose) polymerase