Rapid estrogen signaling negatively regulates PTEN activity through phosphorylation in endometrial cancer cells.
Rapid estrogen signaling negatively regulates PTEN activity through phosphorylation in endometrial cancer cells.
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DOI：
10.1007/s12672-014-0184-z
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发表时间：
2014-08
影响因子：
3
通讯作者：
Jackson TA
中科院分区：
文献类型：
--
作者：
Scully MM;Palacios-Helgeson LK;Wah LS;Jackson TA
子宫内膜癌的危险因素之一。已知17β-雌二醇（E2）在许多生殖组织中刺激基因组和非基因组雌激素受体-α（ERα）作用。然而，转录非依赖性ERα信号在正常和恶性子宫内膜中的作用尚不完全清楚。磷酸酶和张力蛋白同源物（PTEN）是一种肿瘤抑制因子，其主要通过磷酸肌醇3-激酶/AKT信号传导轴的负调节来减少细胞有丝分裂。在月经周期的E2主导的、有丝分裂活跃的增殖期，PTEN水平升高，表明子宫中可能存在PTEN的激素调节。为了确定快速E2信号是否调节PTEN，我们使用ERα阳性、PTEN阳性的子宫内膜细胞。我们发现，胞质E2/ERα信号导致PTEN在关键调控残基处磷酸化增加。重要的是，E2刺激降低了PTEN脂质磷酸酶活性，并导致磷酸化AKT随之增加。我们进一步证明，胞浆ERα以E2依赖的方式与PTEN形成复合物，并且ERα与蛋白激酶2-α（CK 2 α）组成型复合物，CK 2 α是一种先前显示磷酸化PTEN C-末端尾的激酶。这些结果为E2依赖性ERα胞质信号复合物通过羧基端磷酸化负调节PTEN活性提供了机制支持。使用动物模型，我们表明持续的E2信号导致磷酸化PTEN（S380，T382，T383），总PTEN和磷酸化AKT（S473）增加。综上所述，我们提供了一种新的机制，即转录非依赖性E2/ERα信号可能促进子宫内膜中的促肿瘤发生环境。
Hyperestrogenicity is a risk factor for endometrial cancer. 17β-estradiol (E2) is known to stimulate both genomic and nongenomic estrogen receptor-α (ERα) actions in a number of reproductive tissues. However, the contributions of transcription-independent ERα signaling on normal and malignant endometrium are not fully understood. Phosphatase and tensin homolog (PTEN) is a tumor suppressor that decreases cellular mitosis primarily through negative regulation of the phosphoinositide 3-kinase/AKT signaling axis. PTEN levels are elevated during the E2 dominated, mitotically active, proliferative phase of the menstrual cycle, indicating possible hormonal regulation of PTEN in the uterus. In order to determine if rapid E2 signaling regulates PTEN, we used ERα positive, PTEN positive, endometrial cells. We show that cytosolic E2/ERα signaling leads to increased phosphorylation of PTEN at key regulatory residues. Importantly, E2 stimulation decreased PTEN lipid phosphatase activity and caused consequent increases in phospho-AKT. We further demonstrate that cytosolic ERα forms a complex with PTEN in an E2-dependent manner, and that ERα constitutively complexes with protein kinase2-α (CK2α), a kinase previously shown to phosphorylate the C-terminal tail of PTEN. These results provide mechanistic support for an E2-dependent, ERα cytosolic signaling complex that negatively regulates PTEN activity through carboxy terminus phosphorylation. Using an animal model, we show that sustained E2 signaling results in increased phospho-PTEN (S380, T382, T383), total PTEN and phospho-AKT (S473). Taken together, we provide a novel mechanism in which transcription-independent E2/ERα signaling may promote a pro-tumorigenic environment in the endometrium.
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影响因子：
4
作者：
Ganapathy, Vidya;Banach-Petrosky, Whitney;Xie, Wen;Kareddula, Aparna;Nienhuis, Hilde;Miles, Gregory;Reiss, Michael
通讯作者：
Reiss, Michael
影响因子：
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作者：
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影响因子：
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作者：
Filardo, EJ;Quinn, JA;Bland, KI
通讯作者：
Bland, KI
影响因子：
3.8
作者：
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通讯作者：
Seewaldt, Victoria L.