文献类型：期刊文献

英文题名：PPM1K Regulates Hematopoiesis and Leukemogenesis through CDC20-Mediated Ubiquitination of MEIS1 and p21

作者：Liu, Xiaoye[1,2,3];Zhang, Feifei[1,4,5];Zhang, Yaping[1];Li, Xie[6];Chen, Chiqi[1];Zhou, Meiyi[1];Yu, Zhuo[1];Liu, Yunxia[1];Zhao, Yuzheng[6];Hao, Xiaoxin[1];Tang, Yabin[7];Zhu, Liang[7];Liu, Ligen[1];Xie, Li[1];Gu, Hao[1,2,3];Shao, Hongfang[8];Xia, Fangzhen[1];Yin, Chunrong[1];Tao, Minfang[8];Xie, Jingjing[9,10];Zhang, Cheng Cheng[10];Yang, Yi[4,5];Sun, Haipeng[1];Chen, Guo-Qiang[1,2,3];Zheng, Junke[1]

机构：[1]Shanghai Jiao Tong Univ, Sch Med,Dept Pathophysiol, Shanghai Tongren Hosp,Key Lab Cell Differentiat &, Minist Educ,Fac Basic Med,Hongqiao Int Inst Med, Shanghai 200025, Peoples R China;[2]Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Hlth Sci, Shanghai 200031, Peoples R China;[3]Shanghai Jiao Tong Univ, Sch Med, Shanghai 200031, Peoples R China;[4]Shanghai Jiao Tong Univ, Sch Med, Peoples Hosp 9, Dept Ophthalmol, Shanghai, Peoples R China;[5]Shanghai Key Lab Orbital Dis & Ocular Oncol, Shanghai, Peoples R China;[6]East China Univ Sci & Technol, Sch Pharm, State Key Lab Bioreactor Engn, Synthet Biol & Biotechnol Lab, Shanghai 200237, Peoples R China;[7]Shanghai Jiao Tong Univ, Sch Med, Dept Pharmacol, Shanghai 200025, Peoples R China;[8]Shanghai Jiao Tong Univ, Affiliated People Hosp 6, Ctr Reprod Med, Shanghai 200233, Peoples R China;[9]Binzhou Med Univ, Taishan Immunol Program, Yantai 264003, Peoples R China;[10]UT Southwestern Med Ctr, Dept Physiol, Dallas, TX 75390 USA

年份：2018

卷号：23

期号：5

起止页码：1461

外文期刊名：CELL REPORTS

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000432454500018)】；

基金：We appreciate the kind help in the isolation of cortex neural cells provided by Prof. Nanjie Xu and Suya Sun at Shanghai Jiaotong University School of Medicine. BCAA sensors are available from East China University of Science and Technology (ECUST) under a material transfer agreement with Prof. Yi Yang. This work was supported by grants from National Natural Science Foundation of China (81422001, 81570093, 81721004, 81471524, 30971094, 81270317, 81570717, and 81522011), and its innovative group (No. 81721004), the 1000-Youth Elite Program, National Basic Research Program of China (973Program, 2014CB965000, and NO2015CB910403), the NIH (1R01CA172268), CPRIT RP140402, Taishan Scholar Immunology Program, Ministry of Science and Technology of China (2012BAI02B05 and 2013YQ030923), Science and Technology Commission of Shanghai Municipality (14411968300, 13ZR1423300, 16JC1404400, and 17DZ2260100), and Natural Science Foundation of Shanghai (17ZR1415500).

语种：英文

摘要：In addition to acting as building blocks for biosynthesis, aminoacidsmight serve as signalingregulators in various physiological and pathological processes. However, it remains unknown whether amino acid levels affect the activities of hematopoietic stem cells (HSCs). By using a genetically encoded fluorescent sensor of the intracellular levels of branched-chain amino acids (BCAAs), we couldmonitor the dynamics of BCAA metabolism in HSCs. A mitochondrial-targeted 2C-type Ser/Thr protein phosphatase (PPM1K) promotes the catabolism of BCAAs to maintain MEIS1 and p21 levels by decreasing the ubiquitination-mediated degradation controlled by the E3 ubiquitin ligase CDC20. PPM1K deficiency led to a notable decrease in MEIS1/p21 signaling to reduce the glycolysis and quiescence of HSCs, followed by a severe impairment in repopulation activities. Moreover, the deletion of Ppm1k dramatically extended survival in amurine leukemia model. These findings will enhance the current understanding of nutrient signaling in metabolism and function of stem cells.