title: Reversible induction of PARP1 degradation by p53-inducible cis-imidazoline compounds.
abstract: PARP1 is an important enzyme involved in various patho-physiological phenomena such as ischemia/reperfusion (I/R) injury, which occurs when blood flow is restored after cerebral infarction, myocardial infarction and transplantation of various organs. I/R-induced PARP1 over-activation is mediated by production of reactive oxygen species and is involved in NF-κB transactivation. For these reasons, PARP1 is an attractive target for strategies to protect against I/R injury. We previously reported that an MDM2 inhibitor Nutlin3a, a cis-imidazoline compound, induces PARP1 degradation in a p53 and proteasome-dependent manner. In this study, we evaluated the effect of Nutlin3a analogs, Nutlin3b and Caylin2, on PARP1 degradation. Like Nutlin3a, Caylin2, but not Nutlin3b, induced PARP1 degradation in both 3T3-L1 and 3T3-F442A. This result occurred almost in parallel with p53 accumulation. Furthermore Caylin2-induced PARP1 degradation was not observed in p53 deficient mouse embryonic fibroblasts or in the presence of the proteasome inhibitor MG132. These results suggest that Caylin2 induces PARP1 degradation by the same mechanism as Nutlin3a. Finally, we showed that Nutlin3a or Caylin2 treatment induces reversible PARP1 down-regulation without an inflammatory response. For protection against I/R injury, our results support the usability of the p53 inducible cis-imidazoline compounds, Nutlin3a and its analogs, as PARP1 inhibitors.
authors.affiliation: Department of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Yamazaki 2641, Noda, Chiba 278-0022, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Nagai
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Okita
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsumoto
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Okado
authors.forename: Misako
authors.initials: M
authors.lastname: Oku
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Higami
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D015536:Down-Regulation; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C572895:Caylin2; D007093:Imidazoles; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D046988:Proteasome Endopeptidase Complex