Efp targets 14-3-3 sigma for proteolysis and promotes breast tumour growth.
Efp targets 14-3-3 sigma for proteolysis and promotes breast tumour growth.
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发表时间：
2002
期刊：
影响因子：
64.8
通讯作者：
T. Urano;Tomoyuki Saito;T. Tsukui;M. Fujita;T. Hosoi;M. Muramatsu;Y. Ouchi;S. Inoue
中科院分区：
文献类型：
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作者：
T. Urano;Tomoyuki Saito;T. Tsukui;M. Fujita;T. Hosoi;M. Muramatsu;Y. Ouchi;S. Inoue
雌激素通过激活雌激素受体（estrogen receptor, er），并通过其雌激素应答元件调控下游基因，从而对靶器官产生影响。Efp是ER α的靶基因产物，是RING-finger B-box coil -coil （RBCC）基序家族的一员。Efp主要在各种女性器官以及乳腺癌中表达，并且被认为对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。在这里，我们发现Efp是一种环指依赖的泛素连接酶（E3），靶向14-3-3 sigma的蛋白水解，14-3-3 sigma是一种导致G2阻滞的负细胞周期调节因子。我们证明了用反义Efp寡核苷酸治疗乳腺癌MCF7细胞植入雌性胸腺小鼠后，肿瘤生长受到抑制。在没有雌激素的情况下，卵巢切除的胸腺小鼠中过表达efp的MCF7细胞产生肿瘤。小鼠胚胎成纤维细胞中Efp功能的丧失导致14-3-3 sigma的积累，这是导致细胞生长减少的原因。这些数据通过确定14-3-3 sigma是Efp蛋白水解的靶标，从而导致细胞增殖，为了解乳腺癌的细胞周期机制和肿瘤发生提供了新的思路。
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 ER alpha, is a member of the RING-finger B-box coiled-coil (RBCC) motif family. Efp is predominantly expressed in various female organs as well as in breast cancers, and is thought to be essential for oestrogen-dependent cell proliferation and organ development Efp-disrupted mice display underdeveloped uteri and reduced oestrogen responsiveness. Here we show that Efp is a RING-finger-dependent ubiquitin ligase (E3) that targets proteolysis of 14-3-3 sigma, a negative cell cycle regulator that causes G2 arrest. 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 14-3-3 sigma, which is responsible for reduced cell growth. These data provide an insight into the cell-cycle machinery and tumorigenesis of breast cancer by identifying 14-3-3 sigma as a target for proteolysis by Efp, leading to cell proliferation.