Estrogen-mediated upregulation of Noxa is associated with cell cycle progression in estrogen receptor-positive breast cancer cells.
Estrogen-mediated upregulation of Noxa is associated with cell cycle progression in estrogen receptor-positive breast cancer cells.
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DOI：
10.1371/journal.pone.0029466
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Das GM
中科院分区：
文献类型：
--
作者：
Liu W;Swetzig WM;Medisetty R;Das GM
Noxa是Bcl-2同源结构域（BH3）蛋白，据报道是Bcl-2家族的促凋亡成员。雌激素在雌激素受体（ER）阳性乳腺癌细胞中具有刺激细胞生长和抑制细胞凋亡的作用。有趣的是，最近的报道表明，17β-雌二醇（E2）诱导Noxa表达，尽管E2介导的诱导Noxa的机制及其功能意义尚不清楚。以MCF7人乳腺癌细胞为实验模型，我们发现E2通过涉及c-Myc和ERα的p53非依赖性过程上调Noxa。使用小干扰核糖核酸（siRNA）特异性敲低p53、c-Myc和ERα的实验表明，E2治疗后，c-Myc和ERα参与了Noxa的转录上调，而p53不参与。此外，在染色质免疫沉淀（ChIP）试验中，E2促进了c-Myc和er - α向NOXA启动子的募集，E2没有诱导p53的募集。有趣的是，e2介导的Noxa上调与细胞凋亡无关。然而，sirna介导的Noxa敲低导致E2治疗后G0/ g1期细胞周期停滞，并显著延迟g1到s期的转变，这表明在er阳性乳腺癌细胞中，Noxa的表达是细胞周期进展所必需的。
Noxa is a Bcl-2-homology domain (BH3)-only protein reported to be a proapoptotic member of the Bcl-2 family. Estrogen has been well documented to stimulate cell growth and inhibit apoptosis in estrogen receptor (ER)-positive breast cancer cells. Intriguingly, recent reports have shown that 17β-estradiol (E2) induces Noxa expression, although the mechanisms underlying E2-mediated induction of Noxa and its functional significance are unknown. Using MCF7 human breast cancer cells as an experimental model, we show that Noxa is upregulated by E2 via p53-independent processes that involve c-Myc and ERα. Experiments using small interfering ribonucleic acids (siRNA) to specifically knock down p53, c-Myc, and ERα demonstrated that c-Myc and ERα, but not p53, are involved in the transcriptional upregulation of Noxa following E2 treatment. Furthermore, while E2 promoted the recruitment of c-Myc and ERα to the NOXA promoter in chromatin immunoprecipitation (ChIP) assays, E2 did not induce p53 recruitment. Interestingly, E2-mediated upregulation of Noxa was not associated with apoptosis. However, siRNA-mediated knockdown of Noxa resulted in cell cycle arrest in G0/G1-phase and significantly delayed the G1-to-S-phase transition following E2 treatment, indicating that Noxa expression is required for cell cycle progression in ER-positive breast cancer cells.
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