科学研究
DEPTOR is a direct NOTCH1 target that promotes cell proliferation and survival in T-cell leukemia.
编辑:www.4001.com  发布时间:2016-11-15  来源:  阅读次数:
Oncogene.  2016 Sep 5. doi: 10.1038/onc.2016.275. [Epub ahead of print]

DEPTOR is a direct NOTCH1 target that promotes cell proliferation and survival in T-cell leukemia.

Hu Y 1,  Su H 2,  Liu C 1,  Wang Z 1,  Huang L 3,  Wang Q 4,  Liu S 5,  Chen S 4,  Zhou J 3,  Li P 6,  Chen Z 2,  Liu H 7,  Qing G 7.

Author information

  • 1School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
  • 2Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
  • 3Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
  • 4Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, People's Republic of China.
  • 5Department of Pediatric Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
  • 6Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, People's Republic of China.
  • 7Medical Research Institute, Wuhan University, Wuhan, People's Republic of China.

Abstract

Aberrant activation of NOTCH1 signaling plays a vital role in the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL). Yet the molecular events downstream of NOTCH1 that drive T-cell leukemogenesis remain incompletely understood. Starting from genome-wide gene-expression profiling to seek important NOTCH1 transcriptional targets, we identified DEP-domain containing mTOR-interacting protein (DEPTOR), which was previously shown to be important in multiple myeloma but remains functionally unclear in other hematological malignancies. Mechanistically, we demonstrated NOTCH1 directly bound to and activated the human DEPTORpromoter in T-ALL cells. DEPTOR depletion abolished cellular proliferation, attenuated glycolytic metabolism and enhanced cell death, while ectopically expressed DEPTOR significantly promoted cell growth and glycolysis. We further showed that DEPTOR depletion inhibited while its overexpression enhanced AKT activation in T-ALL cells. Importantly, AKT inhibition completely abrogated DEPTOR-mediated cell growth advantages. Moreover, DEPTOR depletion in a human T-ALL xenograft model significantly delayed T-ALL onset and caused a substantial decrease of AKT activation in leukemic blasts. We thus reveal a novel mechanism involved in NOTCH1-driven leukemogenesis, identifying the transcriptional control of DEPTOR and its regulation of AKT as additional key elements of the leukemogenic program activated by NOTCH1.Oncogene advance online publication, 5 September 2016; doi:10.1038/onc.2016.275.

PMID:  
27593934  
DOI:  
10.1038/onc.2016.275

地 址:湖北省武汉市武昌区东湖路115号 邮政编码:430071 电 话:027-68750205  邮 箱:mri@whu.edu.cn

CopyRight© 2016  版权所踊岷澳门百老汇4001登录网站

XML 地图 | Sitemap 地图