Aurora A Kinase Regulates Mammary Epithelial Cell Fate by Determining Mitotic Spindle Orientation in a Notch-Dependent Manner
Aurora A Kinase Regulates Mammary Epithelial Cell Fate by Determining Mitotic Spindle Orientation in a Notch-Dependent Manner
复制标题
DOI：
10.1016/j.celrep.2013.05.044
复制
发表时间：
2013-07-01
期刊：
影响因子：
8.8
通讯作者：
Smalley, Matthew J.
中科院分区：
文献类型：
--
作者：
Regan, Joseph L.;Sourisseau, Tony;Smalley, Matthew J.
乳腺上皮干细胞/祖细胞的子代细胞命运的决定仍然知之甚少。在这里，我们研究了有丝分裂激酶Aurora A （AURKA）在调节乳腺基底和腔系之间的平衡中的作用。我们发现AURKA在基底干细胞中高度表达，并且在较小程度上在管腔祖细胞中表达。野生型AURKA的表达促进了管腔细胞的命运，而S155R突变体的表达减少了增殖，促进了基底命运，并抑制了连续移植。其机制涉及AURKA对有丝分裂纺锤体取向的调控和分裂后子细胞的定位。值得注意的是，这是NOTCH依赖的，因为NOTCH抑制剂阻断了野生型AURKA表达对纺锤体取向的影响，而模仿了S155R突变体的作用。这些发现直接将AURKA、NOTCH信号和有丝分裂纺锤体取向联系起来，并提出了一种调节乳腺管腔和基底谱系平衡的机制。
Cell fate determination in the progeny of mammary epithelial stem/progenitor cells remains poorly understood. Here, we have examined the role of the mitotic kinase Aurora A (AURKA) in regulating the balance between basal and luminal mammary lineages. We find that AURKA is highly expressed in basal stem cells and, to a lesser extent, in luminal progenitors. Wild-type AURKA expression promoted luminal cell fate, but expression of an S155R mutant reduced proliferation, promoted basal fate, and inhibited serial transplantation. The mechanism involved regulation of mitotic spindle orientation by AURKA and the positioning of daughter cells after division. Remarkably, this was NOTCH dependent, as NOTCH inhibitor blocked the effect of wild-type AURKA expression on spindle orientation and instead mimicked the effect of the S155R mutant. These findings directly link AURKA, NOTCH signaling, and mitotic spindle orientation and suggest a mechanism for regulating the balance between luminal and basal lineages in the mammary gland.