Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade
Jianhui Ma, … , Huangxuan Shen, Hongbing Zhang
Jianhui Ma, … , Huangxuan Shen, Hongbing Zhang
Published December 28, 2009
Citation Information: J Clin Invest. 2010;120(1):103-114. https://doi.org/10.1172/JCI37964.
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Research Article

Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade

Abstract

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.

Authors

Jianhui Ma, Yan Meng, David J. Kwiatkowski, Xinxin Chen, Haiyong Peng, Qian Sun, Xiaojun Zha, Fang Wang, Ying Wang, Yanling Jing, Shu Zhang, Rongrong Chen, Lianmei Wang, Erxi Wu, Guifang Cai, Izabela Malinowska-Kolodziej, Qi Liao, Yuqin Liu, Yi Zhao, Qiang Sun, Kaifeng Xu, Jianwu Dai, Jiahuai Han, Lizi Wu, Robert Chunhua Zhao, Huangxuan Shen, Hongbing Zhang

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Figure 10

NF-κB and STAT3/p63 control Notch signaling downstream of mTORC1 in parallel.

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NF-κB and STAT3/p63 control Notch signaling downstream of mTORC1 in para...
(A) WT and Tsc2–/– MEFs were treated with or without 10 nM rapamycin for 24 hours and then subjected to immunoblotting for NF-κB (p65), IκBα, and mTOR signaling. (B) Tsc2–/– MEFs were transfected with p65 siRNA or STAT3 siRNA to knock down p65 or STAT3 expression for 48 hours and were then subjected to immunoblotting for STAT3 and NF-κB signaling. Non–target-directed random siRNA served as a control. (C) Schematic illustration of how NF-κB and STAT3/p63 regulate Notch signaling downstream of mTORC1 in parallel.