Pyruvate kinase M2, but not M1, allele maintains immature metabolic states of murine embryonic stem cells

Regenerative Therapy

Jun Koseki¹  Hiroshi Shima¹  Nobuhiro Tanuma¹  Masamitsu Konno²  Masaki Mori²  Naohiro Nishida²  Yuko Noguchi²  Hideshi Ishii²  Koichi Kawamoto²  Yuichiro Doki²  Miyuki Ozaki²  Kozou Noguchi³  Hiroaki Nagano³  Asuka Nakata⁴  Tatsunori Nishimura⁴  Noriko Gotoh⁴  Hidetoshi Matsui⁵ 

[1] Department of Cancer Profiling Discovery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan;Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan;Department of Gastrointestinal Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan;Division of Cancer Cell Biology, Cancer Research Institute of Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan;Faculty of Mathematics, Kyushu University, Fukuoka 819-0395, Japan;

关键词: Pyruvate kinase;    Embryonic stem cell;    Metabolism;    Differentiation;   

DOI  :  10.1016/j.reth.2015.01.001

来源: DOAJ

【 摘 要 】

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 knock-in 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.

【 授权许可】

Unknown