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

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...

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Published in:The Journal of clinical investigation 2010-01, Vol.120 (1), p.103-114
Main Authors: Ma, Jianhui, Meng, Yan, Kwiatkowski, David J, Chen, Xinxin, Peng, Haiyong, Sun, Qian, Zha, Xiaojun, Wang, Fang, Wang, Ying, Jing, Yanling, Zhang, Shu, Chen, Rongrong, Wang, Lianmei, Wu, Erxi, Cai, Guifang, Malinowska-Kolodziej, Izabela, Liao, Qi, Liu, Yuqin, Zhao, Yi, Sun, Qiang, Xu, Kaifeng, Dai, Jianwu, Han, Jiahuai, Wu, Lizi, Zhao, Robert Chunhua, Shen, Huangxuan, Zhang, Hongbing
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cited_by cdi_FETCH-LOGICAL-c668t-9817f95f8a117a7b7ff9639bfcf319a408b96414000ba1a0e4d886db39f9e1ca3
cites cdi_FETCH-LOGICAL-c668t-9817f95f8a117a7b7ff9639bfcf319a408b96414000ba1a0e4d886db39f9e1ca3
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container_issue 1
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container_title The Journal of clinical investigation
container_volume 120
creator Ma, Jianhui
Meng, Yan
Kwiatkowski, David J
Chen, Xinxin
Peng, Haiyong
Sun, Qian
Zha, Xiaojun
Wang, Fang
Wang, Ying
Jing, Yanling
Zhang, Shu
Chen, Rongrong
Wang, Lianmei
Wu, Erxi
Cai, Guifang
Malinowska-Kolodziej, Izabela
Liao, Qi
Liu, Yuqin
Zhao, Yi
Sun, Qiang
Xu, Kaifeng
Dai, Jianwu
Han, Jiahuai
Wu, Lizi
Zhao, Robert Chunhua
Shen, Huangxuan
Zhang, Hongbing
description 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.
doi_str_mv 10.1172/jci37964
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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.</abstract><cop>United States</cop><pub>American Society for Clinical Investigation</pub><pmid>20038814</pmid><doi>10.1172/jci37964</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record>
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source Open Access: PubMed Central; EZB Electronic Journals Library
subjects Animals
Biomedical research
Breast cancer
Calcium-Binding Proteins - physiology
Cancer
Care and treatment
Cell Differentiation
Cell growth
Cell receptors
Cells, Cultured
Fibroblasts
Health aspects
Humans
Intercellular Signaling Peptides and Proteins - physiology
Jagged-1 Protein
Kidneys
Kinases
Medical prognosis
Membrane Proteins - physiology
Mice
Mice, Inbred BALB C
Mutation
NF-kappa B - physiology
Phosphatidylinositol 3-Kinases - physiology
Physiological aspects
Properties
Protein Kinases - physiology
Receptors, Notch - physiology
Serrate-Jagged Proteins
Signal Transduction - physiology
STAT3 Transcription Factor - physiology
TOR Serine-Threonine Kinases
Transcription Factors - physiology
Tumorigenesis
Tumors
Tyrosine
title Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade
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