Laminin-111 and the Level of Nuclear Actin Regulate Epithelial Quiescence via Exportin-6.
Laminin-111 and the Level of Nuclear Actin Regulate Epithelial Quiescence via Exportin-6.
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DOI：
10.1016/j.celrep.2017.05.050
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发表时间：
2017-06-06
期刊：
影响因子：
8.8
通讯作者：
Bruni-Cardoso A
中科院分区：
文献类型：
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作者：
Fiore APZP;Spencer VA;Mori H;Carvalho HF;Bissell MJ;Bruni-Cardoso A
已知核肌动蛋白（N-actin）参与基因表达的调控。我们之前的研究表明，N-actin水平介导了小鼠上皮细胞对laminin-111 （LN1）的生长和静止反应，laminin-111是乳腺基底膜（BM）的一种成分。我们知道BM在恶性细胞中是有缺陷的，我们在这里展示的是LN1/N-actin通路在人类乳腺癌细胞中是异常的，导致持续生长。光漂白实验显示，在LN1治疗后30分钟，非恶性细胞中的n -肌动蛋白就开始分泌。LN1减弱PI3K通路，导致输出蛋白6 （XPO6）活性上调，并将肌动蛋白转移出细胞核。静音XPO6可防止静音。恶性细胞不受LN1信号的影响。这些结果揭示了LN1在静止和分化中的关键作用，以及LN1/PI3K/XPO6/N-actin轴的缺陷如何解释导致恶性进展的组织稳态和生长控制的丧失。Fiore等人发现，laminin-111 （LN1）在XPO6介导的过程中诱导人乳腺上皮细胞中核肌动蛋白的急剧减少，这是获得细胞静止所必需的。LN1/XPO6/N-actin通路在对LN1无反应且不受控制增殖的恶性细胞中异常。
Nuclear actin (N-actin) is known to participate in the regulation of gene expression. We showed previously that N-actin levels mediate the growth and quiescence of mouse epithelial cells in response to laminin-111 (LN1), a component of the mammary basement membrane (BM). We know that BM is defective in malignant cells, and we show here that it is the LN1/N-actin pathway that is aberrant in human breast cancer cells, leading to continuous growth. Photobleaching assays revealed that N-actin exit in nonmalignant cells begins as early as 30 min after LN1 treatment. LN1 attenuates the PI3K pathway leading to upregulation of exportin-6 (XPO6) activity and shuttles actin out of the nucleus. Silencing XPO6 prevents quiescence. Malignant cells are impervious to LN1 signaling. These results shed light on the crucial role of LN1 in quiescence and differentiation and how defects in the LN1/PI3K/XPO6/N-actin axis explain the loss of tissue homeostasis and growth control that contributes to malignant progression. Fiore et al. show that laminin-111 (LN1) induces a drastic decrease of nuclear actin in human mammary epithelial cells in a process mediated by XPO6 and required for acquisition of cellular quiescence. The LN1/XPO6/N-actin pathway is abnormal in malignant cells that are unresponsive to LN1 and proliferate uncontrollably.
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