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

doi:10.1172/JCI37964

	Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade
	Ma, Jianhui 2,3,4; Meng, Yan 2,3,5; Kwiatkowski, David J.6; Chen, Xinxin 2,3; Feng, Haiyong 2,3; Sun, Qian 2,3; Zha, Xiaojun 2,3; Wang, Fang 2,3; Wang, Ying 2,3; Jing, Yanling 2,3; Zhang, Shu 2,3,7; Chen, Rongrong 2,3; Wang, Lianmei 2,3,8; Wu, Erxi 9; Cai, Guifang 10; Malinowska-Kolodziej, Izabela 6; Liao, Qi 11; Liu, Yuqin 3,12; Zhao, Yi 11; Sun, Qiang 7; Xu, Kaifeng 8; Dai, Jianwu 13; Han, Jiahuai 14; Wu, Lizi 15; Zhao, Robert Chunhua 3,5; Shen, Huangxuan 4; Zhang, Hongbing 1,2,3
	2010
发表期刊	JOURNAL OF CLINICAL INVESTIGATION
ISSN	0021-9738
卷号	120 期号:1 页码:103-114
摘要	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	10.1172/JCI37964
收录类别	SCI
语种	英语
资助项目	National Natural Science Foundation of China[30772466] ; National Natural Science Foundation of China[30788004] ; National Natural Science Foundation of China[30872840] ; National Natural Science Foundation of China[30971503] ; National Basic Research Program of China (973 Program)[2009CB522203] ; National Basic Research Program of China (973 Program)[2009CBS22106] ; Innovation Project of Key Laboratory of Ophthalmology ; NIH National Cancer Institute[1P01CA120964]
WOS研究方向	Research & Experimental Medicine
WOS类目	Medicine, Research & Experimental
WOS记录号	WOS:000273495700017
出版者	AMER SOC CLINICAL INVESTIGATION INC
引用统计	被引频次：200[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	http://119.78.100.204/handle/2XEOYT63/12081
专题	中国科学院计算技术研究所期刊论文_英文
通讯作者	Zhang, Hongbing
作者单位	1.Peking Union Med Coll, Inst Basic Med Sci, Dept Physiol, Beijing 100005, Peoples R China 2.Chinese Acad Med Sci, Inst Basic Med Sci, Natl Lab Med Mol Biol, Dept Physiol & Pathophysiol, Beijing 100730, Peoples R China 3.Chinese Acad Med Sci, Sch Basic Med, Beijing 100037, Peoples R China 4.Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, Lab Ocular Genet, State Key Lab Ophthalmol, Guangzhou 510275, Guangdong, Peoples R China 5.Chinese Acad Med Sci, Inst Basic Med Sci, Ctr Excellence Tissue Engn, Beijing 100730, Peoples R China 6.Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Translat Med,Dept Med, Boston, MA 02115 USA 7.Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Surg, Div Breast Surg, Beijing 100037, Peoples R China 8.Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Med, Div Resp Med, Beijing 100037, Peoples R China 9.N Dakota State Univ, Dept Pharmaceut Sci, Fargo, ND 58105 USA 10.Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA 11.Chinese Acad Sci, Inst Comp Technol, Ctr Adv Comp Res, Beijing, Peoples R China 12.Chinese Acad Med Sci, Inst Basic Med Sci, Dept Pathol, Beijing 100730, Peoples R China 13.Chinese Acad Sci, Inst Genet & Dev Biol, Key Lab Mol Dev Biol, Beijing, Peoples R China 14.Xiamen Univ, Sch Life Sci, Key Lab, Minist Educ Cell Biol & Tumor Cell Engn, Xiamen, Fujian, Peoples R China 15.Univ Florida, Shands Canc Ctr, Dept Mol Genet & Microbiol, Gainesville, FL USA
推荐引用方式 GB/T 7714	Ma, Jianhui,Meng, Yan,Kwiatkowski, David J.,et al. Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade[J]. JOURNAL OF CLINICAL INVESTIGATION,2010,120(1):103-114.
APA	Ma, Jianhui.,Meng, Yan.,Kwiatkowski, David J..,Chen, Xinxin.,Feng, Haiyong.,...&Zhang, Hongbing.(2010).Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade.JOURNAL OF CLINICAL INVESTIGATION,120(1),103-114.
MLA	Ma, Jianhui,et al."Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade".JOURNAL OF CLINICAL INVESTIGATION 120.1(2010):103-114.