Efp targets 14-3-3σ for proteolysis and promotes breast tumour growth
Efp targets 14-3-3σ for proteolysis and promotes breast tumour growth
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DOI：
10.1038/nature00826
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发表时间：
2002-06-20
期刊：
影响因子：
64.8
通讯作者：
Inoue, S
中科院分区：
文献类型：
--
作者：
Urano, T;Saito, T;Inoue, S
雌激素通过激活雌激素受体（ER）并通过雌激素反应元件调节下游基因对靶器官产生影响。 Efp 是 ERalpha(1-3) 的靶基因产物，是环指 B 盒卷曲螺旋 (RBCC) 基序家族 (4) 的成员。 Efp 主要在各种女性器官 2 以及乳腺癌 5 中表达，并且被认为对于雌激素依赖性细胞增殖和器官发育至关重要 - Efp 破坏的小鼠表现出子宫发育不全和雌激素反应性降低 (6)。在这里，我们证明 Efp 是一种环指依赖性泛素连接酶 (E3)，其目标是 14-3-3sigma 的蛋白水解，14-3-3sigma 是一种导致 G2 停滞的负细胞周期调节因子 (7)。我们证明，通过反义 Efp 寡核苷酸治疗，植入雌性无胸腺小鼠中的乳腺癌 MCF7 细胞的肿瘤生长会减少。去卵巢无胸腺小鼠中 Efp 过表达的 MCF7 细胞在缺乏雌激素的情况下会产生肿瘤。小鼠胚胎成纤维细胞中 Efp 功能的丧失会导致 14-3-3sigma 的积累，从而导致细胞生长减少。这些数据将 14-3-3sigma 确定为 Efp 蛋白水解的靶标，从而导致细胞增殖，从而深入了解乳腺癌的细胞周期机制和肿瘤发生。
Oestrogen exerts its influence on target organs through activating oestrogen receptors (ERs) and regulating downstream genes by means of their oestrogen-responsive elements. Efp, a target gene product of ERalpha(1-3), is a member of the RING-finger B-box coiled-coil (RBCC) motif family(4). Efp is predominantly expressed in various female organs 2 as well as in breast cancers 5, and is thought to be essential for oestrogen-dependent cell proliferation and organ development-Efp-disrupted mice display underdeveloped uteri and reduced oestrogen responsiveness(6). Here we show that Efp is a RING-finger-dependent ubiquitin ligase (E3) that targets proteolysis of 14-3-3sigma, a negative cell cycle regulator that causes G2 arrest(7). We demonstrate that tumour growth of breast cancer MCF7 cells implanted in female athymic mice is reduced by treatment with antisense Efp oligonucleotide. Efp-overexpressing MCF7 cells in ovariectomized athymic mice generate tumours in the absence of oestrogen. Loss of Efp function in mouse embryonic fibroblasts results in an accumulation of 14-3-3sigma, which is responsible for reduced cell growth. These data provide an insight into the cell-cycle machinery and tumorigenesis of breast cancer by identifying 14-3-3sigma as a target for proteolysis by Efp, leading to cell proliferation.