CUZD1 is a critical mediator of the JAK/STAT5 signaling pathway that controls mammary gland development during pregnancy.
CUZD1 is a critical mediator of the JAK/STAT5 signaling pathway that controls mammary gland development during pregnancy.
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DOI：
10.1371/journal.pgen.1006654
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发表时间：
2017-03
期刊：
影响因子：
4.5
通讯作者：
Bagchi MK
中科院分区：
文献类型：
--
作者：
Mapes J;Li Q;Kannan A;Anandan L;Laws M;Lydon JP;Bagchi IC;Bagchi MK
在乳腺中，由雌激素、孕激素和催乳素控制的遗传回路与表皮生长因子家族成员调节的途径协同作用，以协调青春期、妊娠期和哺乳期的生长和形态发生。然而，激素和生长因子途径之间相互作用的确切机制仍然知之甚少。我们已经确定了CUB和透明质酸样结构域蛋白1（CUZD 1），表达在乳腺导管和肺泡上皮细胞，作为一种新的调解人的乳腺增生和分化在怀孕和哺乳期。cuzd 1基因缺失的小鼠在妊娠期间表现出乳腺导管分支和肺泡发育的显著障碍，导致随后的哺乳缺陷。乳腺上皮的基因表达谱显示，CUZD 1调节EGF家族生长因子，epiregulin，neuregulin-1和epigen的一个子集的表达，其以自分泌方式激活ErbB 1和ErbB 4受体。蛋白质组学研究进一步揭示了CUZD 1与含有JAK 1/JAK 2和STAT 5的复合物相互作用，JAK 1/JAK 2和STAT 5是乳腺中催乳素信号传导的下游转导物。在没有CUZD 1的情况下，在肺泡形成过程中乳腺上皮中的STAT 5磷酸化被废除。相反，乳腺上皮细胞中Cuzd 1的表达升高刺激了催乳素诱导的STAT 5磷酸化和核转位。染色质免疫沉淀证实了磷酸化STAT 5和CUZD 1在上皮细胞增殖的潜在调节因子epiregulin和上皮细胞分化的标志物乳清酸性蛋白的调节区域中的共同占有。总的来说，这些研究结果表明，CUZD 1在催乳素诱导的JAK/STAT 5信号传导中起着关键作用，该信号传导控制着肺泡发育过程中参与乳腺上皮增殖和分化的关键STAT 5靶基因的表达。在乳腺中，由激素、雌激素、孕激素和催乳素控制的遗传回路与由表皮生长因子家族成员调节的途径协同作用，以协调青春期、妊娠期和哺乳期的生长和形态发生。我们已经确定CUZD 1作为一种新的调解人催乳素信号在类固醇激素引发的小鼠乳腺在怀孕和哺乳期。cuzd 1基因缺失的小鼠在妊娠期间表现出明显的导管分支和肺泡发育障碍，导致随后的哺乳缺陷。给药催乳素未能诱导Cuzd 1基因敲除小鼠乳腺上皮细胞增殖。蛋白质结合研究表明，CUZD 1与催乳素信号传导的下游转导子JAK 1/JAK 2和STAT 5相互作用。此外，乳腺上皮细胞中Cuzd 1的表达升高刺激STAT 5的磷酸化和核转位。因此，CUZD 1是控制乳腺肺泡发育的催乳素的关键介质。
In the mammary gland, genetic circuits controlled by estrogen, progesterone, and prolactin, act in concert with pathways regulated by members of the epidermal growth factor family to orchestrate growth and morphogenesis during puberty, pregnancy and lactation. However, the precise mechanisms underlying the crosstalk between the hormonal and growth factor pathways remain poorly understood. We have identified the CUB and zona pellucida-like domain-containing protein 1 (CUZD1), expressed in mammary ductal and alveolar epithelium, as a novel mediator of mammary gland proliferation and differentiation during pregnancy and lactation. Cuzd1-null mice exhibited a striking impairment in mammary ductal branching and alveolar development during pregnancy, resulting in a subsequent defect in lactation. Gene expression profiling of mammary epithelium revealed that CUZD1 regulates the expression of a subset of the EGF family growth factors, epiregulin, neuregulin-1, and epigen, which act in an autocrine fashion to activate ErbB1 and ErbB4 receptors. Proteomic studies further revealed that CUZD1 interacts with a complex containing JAK1/JAK2 and STAT5, downstream transducers of prolactin signaling in the mammary gland. In the absence of CUZD1, STAT5 phosphorylation in the mammary epithelium during alveologenesis was abolished. Conversely, elevated expression of Cuzd1 in mammary epithelial cells stimulated prolactin-induced phosphorylation and nuclear translocation of STAT5. Chromatin immunoprecipitation confirmed co-occupancy of phosphorylated STAT5 and CUZD1 in the regulatory regions of epiregulin, a potential regulator of epithelial proliferation, and whey acidic protein, a marker of epithelial differentiation. Collectively, these findings suggest that CUZD1 plays a critical role in prolactin-induced JAK/STAT5 signaling that controls the expression of key STAT5 target genes involved in mammary epithelial proliferation and differentiation during alveolar development. In the mammary gland, genetic circuits controlled by the hormones, estrogen, progesterone and prolactin, act in concert with pathways regulated by members of the epidermal growth factor family to orchestrate growth and morphogenesis during puberty, pregnancy and lactation. We have identified CUZD1 as a novel mediator of prolactin signaling in the steroid hormone-primed mouse mammary gland during pregnancy and lactation. Cuzd1-null mice exhibited a striking impairment in ductal branching and alveolar development during pregnancy, resulting in a subsequent defect in lactation. Administration of prolactin failed to induce proliferation of the mammary epithelium in Cuzd1-null mice. Protein binding studies revealed that CUZD1 interacts with downstream transducers of prolactin signaling, JAK1/JAK2 and STAT5. Additionally, elevated expression of Cuzd1 in mammary epithelial cells stimulated phosphorylation and nuclear translocation of STAT5. CUZD1, therefore, is a critical mediator of prolactin that controls mammary alveolar development.