Department of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Yamazaki 2641, Noda, Chiba 278-0022, Japan.
Biochem Biophys Res Commun. 2012 Apr 27;421(1):15-9. doi: 10.1016/j.bbrc.2012.03.091. Epub 2012 Mar 23.
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.
聚腺苷二磷酸核糖聚合酶 1（PARP1）是一种重要的酶，参与多种病理生理现象，如缺血/再灌注（I/R）损伤，这种损伤发生在脑梗死、心肌梗死和各种器官移植后血流恢复时。I/R 诱导的 PARP1 过度激活是由活性氧的产生介导的，并涉及 NF-κB 的反式激活。由于这些原因，PARP1 是一种有吸引力的靶点，可用于保护免受 I/R 损伤。我们之前报道过，MDM2 抑制剂 Nutlin3a（一种顺式咪唑啉化合物）以依赖 p53 和蛋白酶体的方式诱导 PARP1 降解。在这项研究中，我们评估了 Nutlin3a 类似物 Nutlin3b 和 Caylin2 对 PARP1 降解的影响。与 Nutlin3a 一样，Caylin2 而非 Nutlin3b 在 3T3-L1 和 3T3-F442A 中均诱导 PARP1 降解。这一结果几乎与 p53 积累同时发生。此外，在缺乏 p53 的小鼠胚胎成纤维细胞中或在蛋白酶体抑制剂 MG132 的存在下，未观察到 Caylin2 诱导的 PARP1 降解。这些结果表明，Caylin2 通过与 Nutlin3a 相同的机制诱导 PARP1 降解。最后，我们表明，Nutlin3a 或 Caylin2 处理诱导 PARP1 的可逆下调而没有炎症反应。为了防止 I/R 损伤，我们的结果支持使用 p53 诱导的顺式咪唑啉化合物 Nutlin3a 及其类似物作为 PARP1 抑制剂。
