SAG/RBX2 is a novel substrate of NEDD4-1 E3 ubiquitin ligase and mediates NEDD4-1 induced chemosensitization.
SAG/RBX2 is a novel substrate of NEDD4-1 E3 ubiquitin ligase and mediates NEDD4-1 induced chemosensitization.
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DOI：
10.18632/oncotarget.2246
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发表时间：
2014-08-30
期刊：
影响因子：
--
通讯作者：
Sun Y
中科院分区：
文献类型：
--
作者：
Zhou W;Xu J;Zhao Y;Sun Y
细胞凋亡敏感基因（SAG），也称为RBX 2、ROC 2或RNF 7，是SCF E3泛素连接酶的RING组分，通过泛素化和降解许多蛋白质底物来调节细胞功能。虽然我们以前的研究表明，SAG是由氧化还原，有丝分裂原和缺氧通过AP-1和HIF-1的转录诱导，它是完全未知的是否和如何SAG泛素化和降解。在这里，我们报告，NEDD 4 -1，一个HECT结构域的E3泛素连接酶，通过其HECT结构域直接与SAG的C-末端RING结构域结合，并泛素化SAG蛋白酶体介导的降解。一致地，SAG蛋白半衰期分别通过NEDD 4 -1过表达或沉默而缩短或延长。我们还发现SAG通过其C-末端桥接NEDD 4 -1，通过其N-末端桥接CUL-5，形成NEDD 4 -1/SAG/CUL-5三元复合物。在生物学上，NEDD 4 -1过表达通过靶向降解降低SAG水平使癌细胞对依托泊苷诱导的凋亡敏感。因此，SAG被添加到越来越多的NEDD 4 -1底物列表中，并介导其生物学功能。
Sensitive to apoptosis gene (SAG), also known as RBX2, ROC2, or RNF7, is a RING component of SCF E3 ubiquitin ligases, which regulates cellular functions through ubiquitylation and degradation of many protein substrates. Although our previous studies showed that SAG is transcriptionally induced by redox, mitogen and hypoxia via AP-1 and HIF-1, it is completely unknown whether and how SAG is ubiquitylated and degraded. Here we report that NEDD4-1, a HECT domain-containing E3 ubiquitin ligase, binds via its HECT domain directly with SAG's C-terminal RING domain and ubiquitylates SAG for proteasome-mediated degradation. Consistently, SAG protein half-life is shortened or extended by NEDD4-1 overexpression or silencing, respectively. We also found that SAG bridges NEDD4-1 via its C-terminus and CUL-5 via its N-terminus to form a NEDD4-1/SAG/CUL-5 tri-complex. Biologically, NEDD4-1 overexpression sensitizes cancer cells to etoposide-induced apoptosis by reducing SAG levels through targeted degradation. Thus, SAG is added to a growing list of NEDD4-1 substrates and mediates its biological function.
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影响因子：
4.4
作者：
Kumar, S;Harvey, KF;Jenkins, NA
通讯作者：
Jenkins, NA
DOI：
10.1073/pnas.0803233105
发表时间：
2008-06-24
影响因子：
11.1
作者：
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通讯作者：
Rotin, Daniela
影响因子：
11.4
作者：
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Rotin, Daniela
影响因子：
7.3
作者：
Cao XR;Lill NL;Boase N;Shi PP;Croucher DR;Shan H;Qu J;Sweezer EM;Place T;Kirby PA;Daly RJ;Kumar S;Yang B
通讯作者：
Yang B
影响因子：
7.8
作者：
Gu, Qingyang;Bowden, G. Tim;Normolle, Daniel;Sun, Yi
通讯作者：
Sun, Yi