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Cell Rep. 2018 May 1;23(5):1461-1475. doi: 10.1016/j.celrep.2018.03.140.

PPM1K Regulates Hematopoiesis and Leukemogenesis through CDC20-Mediated Ubiquitination of MEIS1 and p21.

Author information

1
Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai 200031, China.
2
Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China.
3
Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
4
Synthetic Biology and Biotechnology Laboratory, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
5
Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
6
Centre for Reproductive Medicine, Shanghai Jiao Tong University Affiliated Sixth People Hospital, Shanghai 200233, China.
7
Taishan Immunology Program, Binzhou Medical University, Yantai 264003, China; Department of Physiology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
8
Department of Physiology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
9
Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China.
10
Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: sunhaipeng@shsmu.edu.cn.
11
Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai 200031, China. Electronic address: chengq@shsmu.edu.cn.
12
Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: zhengjunke@shsmu.edu.cn.

Abstract

In addition to acting as building blocks for biosynthesis, amino acids might serve as signaling regulators 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 could monitor 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 a murine leukemia model. These findings will enhance the current understanding of nutrient signaling in metabolism and function of stem cells.

KEYWORDS:

CDC20; MEIS1/p21; PPM1K; branched-chain amino acids; hematopoietic stem cells; leukemia-initiating cells; ubiquitination

PMID:
29719258
DOI:
10.1016/j.celrep.2018.03.140
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