Ret finger protein 2 enhances ionizing radiation-induced apoptosis via degradation of MKT and MDM2
Ret finger protein 2 enhances ionizing radiation-induced apoptosis via degradation of MKT and MDM2
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DOI：
10.1016/j.ejcb.2010.12.001
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发表时间：
2011-05-01
影响因子：
6.6
通讯作者：
Jin, Young Woo
中科院分区：
文献类型：
--
作者：
Joo, Hae Mi;Kim, Ji Young;Jin, Young Woo
Ret 指蛋白 2 (RFP2) 是一种在多种肿瘤类型中经常缺失的基因，编码具有 RING 指、B 盒和卷曲螺旋结构域的蛋白质，属于 RBCC/TRIM 蛋白质家族。尽管RBCC蛋白参与细胞凋亡、增殖、分化和转录调控等多种细胞过程，但RFP2的生物学功能尚未明确。在这里，我们证明细胞中 RFP2 的过度表达通过 MDM2 和 AKT 的蛋白酶体降解诱导细胞凋亡。 RFP2 的表达具有 RING 结构域依赖性 E3 泛素连接酶活性，通过电离辐射剂量和时间依赖性增加，RFP2 过表达会诱导细胞死亡，同时凋亡分子（p53、p21 和 Bax）表达增加。这些结果取决于 RFP2 的 E3 泛素连接酶活性，因为与野生型 RFP2 相比，包含突变 RING 结构域的突变型 RFP2 无法驱动细胞凋亡。我们观察到 RFP2 与 MDM2（p53 肿瘤抑制因子的负调节因子）和 AKT（细胞水平上细胞凋亡抑制的调节因子）形成复合物。此外，我们发现 RFP2 与 MDM2 和 AKT 的相互作用导致 MDM2 和 Ala 在体内和体外泛素化和蛋白酶体降解。因此，这些数据表明辐射导致 RFP2 过度表达，从而通过增加 p53 稳定性并通过 MDM2 和 AICT 降解降低 AKT 激酶活性来增强电离辐射诱导的细胞凋亡。 (C) 2010 爱思唯尔有限公司。版权所有。
Ret finger protein 2 (RFP2), a gene frequently deleted in multiple tumor types, encodes a protein with a RING finger, B-box, and coiled-coil domain that belongs to the RBCC/TRIM protein family. Although RBCC proteins are involved in diverse cellular processes such as apoptosis, proliferation, differentiation, and transcriptional regulation, the biological function of RFP2 has not been well defined. Here, we demonstrate that overexpression of RFP2 in cells induced apoptosis through proteasomal degradation of MDM2 and AKT. The expression of RFP2, which possesses RING domain-dependent E3 ubiquitin ligase activity, was increased by ionizing radiation dose- and time-dependently, and RFP2 overexpression induced cell death with increased expression of apoptotic molecules (p53, p21, and Bax). These results depended on the E3 ubiquitin ligase activity of RFP2 because mutant RFP2, which contains a mutated RING domain, failed to drive apoptosis compared with wild-type RFP2. We observed that RFP2 formed a complex with MDM2, a negative regulator of the p53 tumor suppressor, and AKT, a regulator of apoptosis inhibition at the cellular level. Additionally, we found that the interaction of RFP2 with MDM2 and AKT resulted in ubiquitination and proteasomal degradation of MDM2 and Ala in vivo and in vitro. Thus, these data suggest that irradiation causes RFP2 overexpression, which enhances ionizing radiation-induced apoptosis by increasing p53 stability and decreasing AKT kinase activity through MDM2 and AICT degradation. (C) 2010 Elsevier GmbH. All rights reserved.