Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade
Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade
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雷帕霉素的哺乳动物靶标通过 STAT3/p63/Jagged/Notch 级联调节小鼠和人类细胞分化。
DOI：
10.1172/jci37964
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发表时间：
2010-01-01
影响因子：
15.9
通讯作者：
Zhang, Hongbing
中科院分区：
文献类型：
--
作者：
Ma, Jianhui;Meng, Yan;Zhang, Hongbing
受体酪氨酸激酶/PI 3 K/AKT/哺乳动物雷帕霉素靶蛋白（RTK/PI 3 K/AKT/mTOR）通路在癌症中经常发生改变，但通过激活mTOR导致肿瘤发生的潜在机制仍不清楚。在这里，我们表明mTOR是小鼠和人类细胞中Notch信号传导的正调节剂，通过诱导STAT 3/p63/Jagged信号级联起作用。此外，在响应来自mTOR的差异提示时，我们发现Notch作为分子开关来改变细胞增殖和分化之间的平衡。我们确定过度活跃的mTOR信号通过增强Notch信号而损害鼠胚胎成纤维细胞的细胞分化。在低分化但高分化的人乳腺癌中，升高的mTOR信号传导与增强的Notch信号传导强烈相关。人肺淋巴管平滑肌瘤病（LAM）和由于肿瘤抑制因子TSC 1或TSC 2缺陷而具有过度活跃的mTOR的小鼠肾肿瘤都表现出增强的STAT 3/p63/Notch信号传导。此外，具有不受控制的mTOR信号传导的细胞的致瘤潜力被Notch抑制抑制。因此，我们的数据表明，增强的Notch信号传导对细胞分化的干扰可能是某些具有异常激活的RTK/PI 3 K/AKT/mTOR通路的肿瘤显示的分化不足表型的原因。此外，STAT 3/p63/Notch轴可能是治疗表现出过度活跃的mTOR信号传导的癌症的有用靶标。
The receptor tyrosine kinase/PI3K/AKT/mammalian target of rapamycin (RTK/PI3K/AKT/mTOR) pathway is frequently altered in cancer, but the underlying mechanism leading to tumorigenesis by activated mTOR remains less clear. Here we show that mTOR is a positive regulator of Notch signaling in mouse and human cells, acting through induction of the STAT3/p63/Jagged signaling cascade. Furthermore, in response to differential cues from mTOR, we found that Notch served as a molecular switch to shift the balance between cell proliferation and differentiation. We determined that hyperactive mTOR signaling impaired cell differentiation of murine embryonic fibroblasts via potentiation of Notch signaling. Elevated mTOR signaling strongly correlated with enhanced Notch signaling in poorly differentiated but not in well-differentiated human breast cancers. Both human lung lymphangioleiomyomatosis (LAM) and mouse kidney tumors with hyperactive mTOR due to tumor suppressor TSC1 or TSC2 deficiency exhibited enhanced STAT3/p63/Notch signaling. Furthermore, tumorigenic potential of cells with uncontrolled mTOR signaling was suppressed by Notch inhibition. Our data therefore suggest that perturbation of cell differentiation by augmented Notch signaling might be responsible for the underdifferentiated phenotype displayed by certain tumors with an aberrantly activated RTK/PI3K/AKT/mTOR pathway. Additionally, the STAT3/p63/Notch axis may be a useful target for the treatment of cancers exhibiting hyperactive mTOR signaling.