Zinc Finger Homeodomain Factor Zfhx3 Is Essential for Mammary Lactogenic Differentiation by Maintaining Prolactin Signaling Activity
Zinc Finger Homeodomain Factor Zfhx3 Is Essential for Mammary Lactogenic Differentiation by Maintaining Prolactin Signaling Activity
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锌指同源域因子 Zfhx3 通过维持催乳素信号活性对于乳腺泌乳分化至关重要
DOI：
10.1074/jbc.m116.719377
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发表时间：
2016-06-10
影响因子：
4.8
通讯作者：
Dong, Jin-Tang
中科院分区：
文献类型：
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作者：
Zhao, Dan;Ma, Gui;Dong, Jin-Tang
锌指同源异型盒3（ZFHX 3，ATBF 1）是一种抑制前列腺癌发生并诱导神经元分化的转录因子。它还与雌激素受体α相互作用，抑制细胞增殖，调节小鼠青春期乳腺发育。在本研究中，我们研究了Zfhx 3是否以及如何调节小鼠乳腺的催乳分化。Zfhx 3蛋白在乳腺发育的不同阶段均有不同程度的表达，泌乳期表达量最高。在HC 11小鼠乳腺上皮细胞系中，在体外模型的催乳，敲低Zfhx 3衰减催乳素诱导的β-酪蛋白的表达和形态学变化，催乳分化的指标。在小鼠乳腺组织中，Zfhx 3的敲除中断了泌乳，导致腺体发育不全，肺泡更小更少，β-酪蛋白表达减少，分娩后管腔细胞中大量细胞质脂滴积累，以及泌乳失败。从机制上讲，Zfhx 3维持了Prlr（催乳素受体）的表达和Prlr-Jak 2-Stat 5信号传导活性，而在HC 11细胞和乳腺组织中敲低和敲除Zfhx 3分别降低了Prlr表达、Stat 5磷酸化和Prlr-Jak 2-Stat 5靶基因的表达。这些发现表明，Zfhx 3在乳腺的适当催乳发育中起着至关重要的作用，至少部分是通过维持Prlr表达和Prlr-Jak 2-Stat 5信号传导活性。
The zinc finger homeobox 3 (ZFHX3, also named ATBF1 for AT motif binding factor 1) is a transcription factor that suppresses prostatic carcinogenesis and induces neuronal differentiation. It also interacts with estrogen receptor alpha to inhibit cell proliferation and regulate pubertal mammary gland development in mice. In the present study, we examined whether and how Zfhx3 regulates lactogenic differentiation in mouse mammary glands. At different stages of mammary gland development, Zfhx3 protein was expressed at varying levels, with the highest level at lactation. In the HC11 mouse mammary epithelial cell line, an in vitro model of lactogenesis, knockdown of Zfhx3 attenuated prolactin-induced beta-casein expression and morphological changes, indicators of lactogenic differentiation. In mouse mammary tissue, knock-out of Zfhx3 interrupted lactogenesis, resulting in underdeveloped glands with much smaller and fewer alveoli, reduced beta-casein expression, accumulation of large cytoplasmic lipid droplets in luminal cells after parturition, and failure in lactation. Mechanistically, Zfhx3 maintained the expression of Prlr (prolactin receptor) and Prlr-Jak2-Stat5 signaling activity, whereas knockdown and knock-out of Zfhx3 in HC11 cells and mammary tissues, respectively, decreased Prlr expression, Stat5 phosphorylation, and the expression of Prlr-Jak2-Stat5 target genes. These findings indicate that Zfhx3 plays an essential role in proper lactogenic development in mammary glands, at least in part by maintaining Prlr expression and Prlr-Jak2-Stat5 signaling activity.