Accumulation of p53 via down-regulation of UBE2D family genes is a critical pathway for cadmium-induced renal toxicity.
Accumulation of p53 via down-regulation of UBE2D family genes is a critical pathway for cadmium-induced renal toxicity.
复制标题
通过UBE2D家族基因下调p53的积累是镉诱导的肾脏毒性的关键途径。
DOI：
10.1038/srep21968
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发表时间：
2016-02-25
影响因子：
4.6
通讯作者：
Satoh M
中科院分区：
文献类型：
--
作者：
Lee JY;Tokumoto M;Fujiwara Y;Hasegawa T;Seko Y;Shimada A;Satoh M
慢性镉（Cd）暴露可引起肾毒性。在镉的肾毒性中，p53被认为参与其中。我们前期的研究表明，镉下调UBE 2D（泛素结合酶E2 D）家族成员的基因表达。在这里，我们的目的是确定UBE 2D家族成员和p53依赖性细胞凋亡的人近端肾小管细胞（HK-2细胞）镉处理之间的关联。镉通过抑制YY 1和FOXF 1转录因子的活性，增加细胞内p53蛋白水平，降低UBE 2D 2和UBE 2D 4基因的表达。UBE 2D 2和UBE 2D 4的双敲除引起p53蛋白水平的增加，并且p53的敲除不仅减弱了Cd诱导的凋亡，而且减弱了Cd诱导的凋亡相关基因（BAX和BTAA）的表达。此外，小鼠暴露于镉6个月导致近端肾小管细胞中p53水平升高和凋亡诱导。这些结果表明，UBE 2D家族基因的下调，随后在近端肾小管细胞中积累的p53是镉诱导的肾毒性的一个重要机制。
Chronic cadmium (Cd) exposure can induce renal toxicity. In Cd renal toxicity, p53 is thought to be involved. Our previous studies showed that Cd down-regulated gene expression of the UBE2D (ubiquitin-conjugating enzyme E2D) family members. Here, we aimed to define the association between UBE2D family members and p53-dependent apoptosis in human proximal tubular cells (HK-2 cells) treated with Cd. Cd increased intracellular p53 protein levels and decreased UBE2D2 and UBE2D4 gene expression via inhibition of YY1 and FOXF1 transcription factor activities. Double knockdown of UBE2D2 and UBE2D4 caused an increase in p53 protein levels, and knockdown of p53 attenuated not only Cd-induced apoptosis, but also Cd-induced apoptosis-related gene expression (BAX and PUMA). Additionally, the mice exposed to Cd for 6 months resulted in increased levels of p53 and induction of apoptosis in proximal tubular cells. These findings suggest that down-regulation of UBE2D family genes followed by accumulation of p53 in proximal tubular cells is an important mechanism for Cd-induced renal toxicity.