Downregulation of ubiquitin E3 ligase TNF receptor-associated factor 7 leads to stabilization of p53 in breast cancer
Downregulation of ubiquitin E3 ligase TNF receptor-associated factor 7 leads to stabilization of p53 in breast cancer
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泛素 E3 连接酶 TNF 受体相关因子 7 的下调导致乳腺癌中 p53 的稳定
DOI：
10.3892/or.2012.2121
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发表时间：
2013-01-01
期刊：
影响因子：
4.2
通讯作者：
Liu, Sijin
中科院分区：
文献类型：
--
作者：
Wang, Lixin;Wang, Lei;Liu, Sijin
P53是一种关键的肿瘤抑制因子，也是多种信号通路的主要调节者，如与细胞凋亡、细胞周期和DNA修复相关的信号通路。在这项研究中，我们发现在一组乳腺癌标本中有明显的P53蛋白胞浆积聚。一些突变通过破坏MDM2介导的P53降解而导致P53积聚。然而，基因测序显示，在我们的大多数样本中没有p53突变。通过mRNA和蛋白表达分析寻找其他可能的p53 E3连接酶，发现这些乳腺肿瘤中肿瘤坏死因子受体相关因子7(TRAF7)的表达下调。我们进一步确定TRAF7是体外K4-8连接的P53泛素化的E3连接酶。这些结果表明，P53的积聚是由于TRAF7介导的泛素化缺陷所致。在乳腺癌队列中，TRAF7的下调也与预后不良有关。总而言之，TRAF7介导的P53泛素化在乳腺癌的发展中起着关键作用，这些见解可能有助于开发乳腺癌的新治疗策略。
p53 is a key tumor suppressor and a master regulator of various signaling pathways, such as those related to apoptosis, cell cycle and DNA repair. In this study, we found a pronounced cytosolic accumulation of the p53 protein in a panel of breast cancer specimens. Several mutations lead to p53 accumulation by disruption of MDM2-mediated p53 degradation. However, gene sequencing revealed no p53 mutation in the majority of our samples. Through search for other possible p53 E3 ligases by mRNA and protein expression analysis, down regulation of TNF receptor-associated factor 7 (TRAF7) expression was found in these breast tumors. We further identified TRAF7 as an E3 ligase for K4-8-linked ubiquitination of p53 in vitro. These results suggested that the p53 accumulation was due to the defects of TRAF7-mediated ubiquitination. The down regulation of TRAF7 also correlated with poor prognosis in a breast cancer cohort. Collectively, TRAF7-mediated ubiquitination of p53 plays a critical role in breast cancer development, and these insights may aid in the development of novel therapeutic strategies for breast cancer.