l-Threonine Regulates G1/S Phase Transition of Mouse Embryonic Stem Cells via PI3K/Akt, MAPKs, and mTORC Pathways

Ryu, Jung Min; Han, Ho Jae

doi:10.1074/jbc.m110.216283

Cited by 72 publications

(74 citation statements)

References 37 publications

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“…In vivo experiments of fasting and refeeding have recently shown the activation of Akt in the liver of refed mice, and experiments with liver-specific rictor knockout mice demonstrated mTORC2 dependence (34). Interestingly, the addition of L-threonine induced the proliferation of mouse embryonic stem cells through phosphorylation of Akt, p38, c-Jun N-terminal kinase/stress-activated protein kinase, and mTOR proteins (35). In this paper, the use of phospho-specific antibodies against regulatory proteins of the PI3K and p38 signaling pathways, in combination with the use of specific inhibitors, knockdown experiments, and kinase assays, allowed us to show that the increase in glycolytic metabolism after stimulation by amino acids converges with Akt activation.…”

Section: Discussionmentioning

confidence: 99%

Akt-dependent Activation of the Heart 6-Phosphofructo-2-kinase/Fructose-2,6-bisphosphatase (PFKFB2) Isoenzyme by Amino Acids

Novellasdemunt

Tato

Navarro-Sabaté

et al. 2013

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Akt-dependent Activation of the Heart 6-Phosphofructo-2-kinase/Fructose-2,6-bisphosphatase (PFKFB2) Isoenzyme by Amino Acids

Novellasdemunt

Tato

Navarro-Sabaté

et al. 2013

Journal of Biological Chemistry

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“…34 Gln is metabolized to pyruvate through glutaminolysis, which can contribute significantly to cellular metabolism under some conditions. [6][7] Our results show that inhibition of glutaminolysis via a glutaminase inhibitor eliminates Gln-induced mESC proliferation, suggesting that Gln has an important role in the regulation of stem cell proliferation, which is mediated by Gln metabolites rather than by Gln itself.…”

Section: Discussionmentioning

confidence: 99%

Glutamine contributes to maintenance of mouse embryonic stem cell self-renewal through PKC-dependent downregulation of HDAC1 and DNMT1/3a

2015

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(2015) Glutamine contributes to maintenance of mouse embryonic stem cell self-renewal through PKCdependent downregulation of HDAC1 and DNMT1/3a, Cell Cycle, 14:20, 3292-3305, DOI: 10.1080/15384101.2015 Although glutamine (Gln) is not an essential amino acid, it is considered a critical substrate in many key metabolic processes that control a variety of physiological functions and are involved in regulating early embryonic development. Thus, we investigated the effect of Gln on regulation of mouse embryonic stem cell (mESC) self-renewal and related signaling pathways. Gln deprivation decreased Oct4 expression as well as expression of cell cycle regulatory proteins. However, Gln treatment retained the expression of cell cycle regulatory proteins and the Oct4 in mESCs, which were blocked by compound 968 (a glutaminase inhibitor). In addition, Gln stimulated PI3K/Akt pathway, which subsequently elicited PKCe translocation to membrane without an influx of intracellular Ca 2+ . Inhibition of Akt and PKC blocked Glninduced Oct4 expression and proliferation. Gln also stimulated mTOR phosphorylation in a time-dependent manner, which abolished by PKC inhibition. Furthermore, Gln increased the cellular population of both Oct4 and bromodeoxyuridine positive cells, suggesting that Gln regulates self-renewal ability of mESCs. Gln induced a decrease in HDAC1, but not in HDAC2, which were blocked by PKC inhibitors. Gln treatment resulted in an increase in global histone acetylation and methylation. In addition, Gln significantly reduced methylation of the Oct4 promoter region through decrease in DNMT1 and DNMT3a expression, which were blocked by PKC and HDAC inhibitors. In conclusion, Gln stimulates mESC proliferation and maintains mESC undifferentiation status through transcription regulation via the Akt, PKCe, and mTOR signaling pathways.

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“…Pluripotent mESCs are dependent on threonine catabolism by threonine dehydrogenase (TDH) for the synthesis of SAM, which in turn regulates histone methylations that drive ESC self-renewal and pluripotency ShyhChang et al, 2013). This process appears to be dependent on PI3K/ AKT/mTOR signalling, as inhibition of this signalling attenuates the effect (Ryu and Han, 2011). However, TDH is inactive in hESCs owing to genetic mutations in human; thus, it is unclear how hESCs, particularly the fast growing naive hESCs, circumvent TDH deficiency.…”

Section: (Box 2)mentioning

confidence: 99%

Proliferation, survival and metabolism: the role of PI3K/AKT/mTOR signalling in pluripotency and cell fate determination

2016

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Phosphatidylinositide 3 kinases (PI3Ks) and their downstream mediators AKT and mammalian target of rapamycin (mTOR) constitute the core components of the PI3K/AKT/mTOR signalling cascade, regulating cell proliferation, survival and metabolism. Although these functions are well-defined in the context of tumorigenesis, recent studies -in particular those using pluripotent stem cells -have highlighted the importance of this pathway to development and cellular differentiation. Here, we review the recent in vitro and in vivo evidence for the role PI3K/AKT/mTOR signalling plays in the control of pluripotency and differentiation, with a particular focus on the molecular mechanisms underlying these functions.

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l-Threonine Regulates G1/S Phase Transition of Mouse Embryonic Stem Cells via PI3K/Akt, MAPKs, and mTORC Pathways

Cited by 72 publications

References 37 publications

Akt-dependent Activation of the Heart 6-Phosphofructo-2-kinase/Fructose-2,6-bisphosphatase (PFKFB2) Isoenzyme by Amino Acids

Akt-dependent Activation of the Heart 6-Phosphofructo-2-kinase/Fructose-2,6-bisphosphatase (PFKFB2) Isoenzyme by Amino Acids

Glutamine contributes to maintenance of mouse embryonic stem cell self-renewal through PKC-dependent downregulation of HDAC1 and DNMT1/3a

Proliferation, survival and metabolism: the role of PI3K/AKT/mTOR signalling in pluripotency and cell fate determination

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