Musashil modulates mammary progenitor cell expansion through proliferin-mediated activation of the Wnt and Notch pathways
Musashil modulates mammary progenitor cell expansion through proliferin-mediated activation of the Wnt and Notch pathways
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DOI：
10.1128/mcb.00040-08
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发表时间：
2008-06-01
影响因子：
5.3
通讯作者：
Glazer, Robert I.
中科院分区：
文献类型：
--
作者：
Wang, Xiao-Yang;Yin, Yuzhi;Glazer, Robert I.
RNA结合蛋白Musashi1(Msi1)是果蝇神经前体细胞和黑腹果蝇Notch介导转录的正调控因子，被认为是一种可能的人类乳腺干细胞标记物。在这里，我们描述了Msi1的一个新的功能角色：它能够驱动祖细胞沿着管腔和肌上皮细胞谱系扩张。乳腺上皮细胞表达Msi1可增加CD24(Hi)、Sca-1(+)、CD24(Hi)、CD29(+)、CK19、CK6和CK14/CK18双阳性祖细胞的表达。细胞增殖与MSI表达细胞条件培养液中的增殖素-1(PLF1)增加和Dickkopf-3(DKK3)分泌减少有关，这与细胞外信号调节激酶(ERK)磷酸化和集落形成增加有关。用MEK抑制剂U0126处理可抑制ERK激活，并降低由Msi1表达引起的Notch和β-连环蛋白/T细胞因子(TCF)报告活性。在对照细胞中，用短发夹状RNA(ShRNA)减少DKK3会增加Notch和β-catenin/TCF的激活，而在表达Msi1的细胞中用shRNA减少PLF1则抑制这些途径。这些结果证实Msi1是乳房谱系的关键决定因素，因为它能够协调细胞周期进入，并通过涉及PLF1和DKK3的新的自分泌过程激活Notch和Wnt通路。
The RNA-binding protein Musashi1 (Msi1) is a positive regulator of Notch-mediated transcription in Drosophila melanogaster and neural progenitor cells and has been identified as a putative human breast stem cell marker. Here we describe a novel functional role for Msi1: its ability to drive progenitor cell expansion along the luminal and myoepithelial lineages. Expression of Msi1 in mammary epithelial cells increases the abundance of CD24(hi) Sca-1(+), CD24(hi) CD29(+), CK19, CK6, and double-positive CK14/CK18 progenitor cells. Proliferation is associated with increased proliferin-1 (PLF1) and reduced Dickkopf-3 (DKK3) secretion into the conditioned medium from Msi-expressing cells, which is associated with increased colony formation and extracellular signal-regulated kinase (ERK) phosphorylation. Treatment with the MEK inhibitor U0126 inhibits ERK activation and decreases Notch and beta-catenin/T-cell factor (TCF) reporter activity resulting from Msi1 expression. Reduction of DKK3 in control cells with a short hairpin RNA (shRNA) increases Notch and beta-catenin/TCF activation, whereas reduction of PLF1 with a shRNA in Msi1-expressing cells inhibits these pathways. These results identify Msi1 as a key determinant of the mammary lineage through its ability to coordinate cell cycle entry and activate the Notch and Wnt pathways by a novel autocrine process involving PLF1 and DKK3.