Beta-catenin and estrogen signaling collaborate to drive cyclin D1 expression in developing mouse prostate.
Beta-catenin and estrogen signaling collaborate to drive cyclin D1 expression in developing mouse prostate.
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DOI：
10.1016/j.diff.2016.11.002
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发表时间：
2017-01
期刊：
影响因子：
--
通讯作者：
Vezina CM
中科院分区：
文献类型：
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作者：
Mulligan WA;Wegner KA;Keil KP;Mehta V;Taketo MM;Vezina CM
雄激素、β-连环蛋白（CTNNB 1）和雌激素途径刺激发育中的小鼠前列腺的增殖生长，但这些途径如何相互作用尚不完全清楚。我们以前发现雄激素诱导CTNNB 1信号在小鼠尿生殖窦（UGS）上皮细胞，前列腺导管上皮细胞来源。其他研究表明，低雌二醇浓度诱导UGS上皮增殖生长。在这里，我们发现CTNNB 1信号与前列腺芽中的细胞周期蛋白D1（CCND 1）表达重叠，我们使用遗传方法来测试CTNNB 1信号是否诱导CCND 1表达。我们观察到一个意想不到的性二态反应过度活跃CCNTB 1信号：在雄性小鼠UGS中，它增加Ccnd 1 mRNA丰度，而不增加其蛋白丰度，但在雌性UGS中，它增加Ccnd 1 mRNA和蛋白丰度，这表明雌激素在稳定CCND 1蛋白的潜在作用。用雄激素和17β-雌二醇或蛋白酶体抑制剂处理野生型雄性UGS外植体增加前列腺芽上皮中的CCND 1蛋白和KI 67标记。总之，我们的研究结果与上皮细胞增殖生长机制相一致，该机制将CTNNB 1驱动的Ccnd 1转录和雌激素介导的CCND 1蛋白稳定化联系起来。
Androgen, beta-catenin (CTNNB1), and estrogen pathways stimulate proliferative growth of developing mouse prostate but how these pathways interact is not fully understood. We previously found that androgens induce CTNNB1 signaling in mouse urogenital sinus (UGS) epithelium from which prostatic ductal epithelium derives. Others have shown that low estradiol concentrations induce UGS epithelial proliferative growth. Here, we found that CTNNB1 signaling overlaps cyclin D1 (CCND1) expression in prostatic buds and we used a genetic approach to test whether CTNNB1 signaling induces CCND1 expression. We observed an unexpected sexually dimorphic response to hyperactive CCNTB1 signaling: in male mouse UGS it increased Ccnd1 mRNA abundance without increasing its protein abundance but in female UGS it increased Ccnd1 mRNA and protein abundance, suggesting a potential role for estrogens in stabilizing CCND1 protein. Treating wild type male UGS explants with androgen and either 17β-estradiol or a proteasome inhibitor increased CCND1 protein and KI67 labeling in prostatic bud epithelium. Together, our results are consistent with an epithelial proliferative growth mechanism linking CTNNB1-driven Ccnd1 transcription and estrogen-mediated CCND1 protein stabilization.