期刊
REGENERATIVE THERAPY
卷 1, 期 -, 页码 63-71出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.reth.2015.01.001
关键词
Pyruvate kinase; Embryonic stem cell; Metabolism; Differentiation
资金
- Ministry of Education, Culture, Sports, Science, and Technology [23390199, 25112708, 25134711, 30253420, 26670604]
- Ministry of Health, Labor, and Welfare [H23-003]
- National Institute of Biomedical Innovation [12-4]
- Osaka University Drug Discovery Funds, Japan
- Kobayashi Cancer Research Foundation
- Princess Takamatsu Cancer Research Fund
- Takeda Science and Medical Research Foundation
- Suzuken Memorial Foundation
- Yasuda Medical Foundation
- Pancreas Research Foundation of Japan
- Chugai Co., Ltd.
- Yakult Honsha Co., Ltd.
- Merck Co., Ltd.
- Unitech Co., Ltd.
- EBM Research Center Inc.
- Taiho Therapeutic Co., Ltd.
- Grants-in-Aid for Scientific Research [26430130, 25730017, 26640072, 15K15496, 26293303, 15H05791, 15H04294, 26670604, 15K15474, 23390199, 15H05664, 25112708] Funding Source: KAKEN
The M2 isoform of pyruvate kinase, the final rate-limiting enzyme of aerobic glycolysis, is expressed during embryonic development. In contrast, the M1 isoform is expressed in differentiated cells due to alternative splicing. Here we investigated murine embryonic stem cells (ESCs) with Pkm1 or Pkm2 knockin alleles. Pkm1 allele knock-in resulted in excessive oxidative phosphorylation and induced the formation of cysteine-thiol disulfide-dependent complexes of forkhead box class-O (FOXO) transcription factors, which resulted in altered endoderm differentiation. In contrast, Pkm2 knock-in induced synthesis of a methylation-donor, S-adenosylmethionine, and increased unsaturated eicosanoid groups, which contributed to the redox control and maintenance of ESC undifferentiated status. Because PKM2 is also a critical enzyme for the cancer-specific Warburg effect, our results demonstrate an important role for the Pkm2 allele in establishing intracellular redox conditions and modulating PKM1-dependent oxidative phosphorylation events to achieve an appropriate ESC differentiation program. (C) 2015, The Japanese Society for Regenerative Medicine. Production and hosting by Elsevier B.V. All rights reserved.
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