Autophagy Regulates Homeostasis of Pluripotency-Associated Proteins in hESCs

Cho, Yun-Hee; Han, Kyu Min; Kim, Dong Kyu; Lee, Joonsun; Lee, Sangeun; Choi, Kyeng-Won; Kim, Jungho; Han, Yong Mahn

doi:10.1002/stem.1589

Cited by 57 publications

(34 citation statements)

References 40 publications

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“…Under culture conditions permissive for the propagation of primed ESCs and where there is an abundance of nutrients, autophagy occurs at a basal level and therefore its deficiency has no detrimental effect in both mESCs and hESCs (Mizushima et al, 2001;Cho et al, 2014). However, stress conditions such as starvation act to reduce mTORC1 signalling, leading to the activation of autophagy, which is required to support ESC homeostasis via the expression of pluripotent genes (Mizushima et al, 2001).…”

Section: (Box 2)mentioning

confidence: 99%

“…However, stress conditions such as starvation act to reduce mTORC1 signalling, leading to the activation of autophagy, which is required to support ESC homeostasis via the expression of pluripotent genes (Mizushima et al, 2001). Deficiency of autophagy in ESCs under such stress conditions leads to apoptosis or detrimental accumulation of pluripotency-associated proteins that compromise the pluripotent state (Mizushima et al, 2001;Cho et al, 2014). Expanding on the crucial role of mTORC1 in nutrient sensing, several amino acid pathways have been reported to be essential for the maintenance of PSC properties Carroll et al, 2016;Shiraki et al, 2014;Carey et al, 2015).…”

Section: (Box 2)mentioning

confidence: 99%

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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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Section: (Box 2)mentioning

confidence: 99%

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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“…Given recent findings that mTOR activation can be controlled by the interplay between AKT kinase and AMPK, there is now extensive evidence validating various components of this pathway as potential molecular targets for cancer treatment. Autophagy can induce both cell survival and cell death under nutrient starvation, tumorigenesis including breast cancer,15 neurodegeneration, and other physiological and pathological processes 16,17. The conversion of LC3-I to LC3-II reflects the occurrence of autophagy 18.…”

Section: Introductionmentioning

confidence: 99%

Gemcitabine resistance in breast cancer cells regulated by PI3K/AKT-mediated cellular proliferation exerts negative feedback via the MEK/MAPK and mTOR pathways

Yang¹,

Lin²,

Guo³

et al. 2014

OTT

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Chemoresistance is a major cause of cancer treatment failure and leads to a reduction in the survival rate of cancer patients. Phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) and mitogen-activated protein kinase (MAPK) pathways are aberrantly activated in many malignant tumors, including breast cancer, which may indicate an association with breast cancer chemoresistance. In this study, we generated a chemoresistant human breast cancer cell line, MDA-MB-231/gemcitabine (simplified hereafter as “231/Gem”), from MDA-MB-231 human breast cancer cells. Flow cytometry studies revealed that with the same treatment concentration of gemcitabine, 231/Gem cells displayed more robust resistance to gemcitabine, which was reflected by fewer apoptotic cells and enhanced percentage of S-phase cells. Through the use of inverted microscopy, Cell Counting Kit-8, and Transwell assays, we found that compared with parental 231 cells, 231/Gem cells displayed more morphologic projections, enhanced cell proliferative ability, and improved cell migration and invasion. Mechanistic studies revealed that the PI3K/AKT/mTOR and mitogen-activated protein kinase kinase (MEK)/MAPK signaling pathways were activated through elevated expression of phosphorylated (p)-extracellular signal-regulated kinase (ERK), p-AKT, mTOR, p-mTOR, p-P70S6K, and reduced expression of p-P38 and LC3-II (the marker of autophagy) in 231/Gem in comparison to control cells. However, there was no change in the expression of Cyclin D1 and p-adenosine monophosphate-activated protein kinase (AMPK). In culture, inhibitors of PI3K/AKT and mTOR, but not of MEK/MAPK, could reverse the enhanced proliferative ability of 231/Gem cells. Western blot analysis showed that treatment with a PI3K/AKT inhibitor decreased the expression levels of p-AKT, p-MEK, p-mTOR, and p-P70S6K; however, treatments with either MEK/MAPK or mTOR inhibitor significantly increased p-AKT expression. Thus, our data suggest that gemcitabine resistance in breast cancer cells is mainly mediated by activation of the PI3K/AKT signaling pathway. This occurs through elevated expression of p-AKT protein to promote cell proliferation and is negatively regulated by the MEK/MAPK and mTOR pathways.

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“…Recent work has shown that SOX2-induced suppression of mTOR is necessary for induced pluripotent stem cell generation (8), and although they did not look at DEPTOR, it is plausible that DEPTOR is the intermediate in the process based on our data. Overall, the Deptor-mTOR pathway very likely modulates pluripotency by regulating protein synthesis and autophagy by post-transcriptionally balancing the pluripotency network and repressing the differentiation network (9,30).…”

Section: Discussionmentioning

confidence: 99%

DEPTOR Is a Stemness Factor That Regulates Pluripotency of Embryonic Stem Cells

Agrawal

Reynolds

Chew

et al. 2014

Journal of Biological Chemistry

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Background: DEPTOR is a negative regulator of mTOR activity and thus plays a role in the regulation of cell metabolism and growth. Results: DEPTOR levels decrease upon differentiation of embryonic stem cells, and reduction of DEPTOR levels is sufficient to promote differentiation. Conclusion: DEPTOR is a stemness factor that regulates pluripotency. Significance: Manipulation of DEPTOR activity provides a means of influencing embryonic stem cell renewal and differentiation.

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Autophagy Regulates Homeostasis of Pluripotency-Associated Proteins in hESCs

Cited by 57 publications

References 40 publications

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

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

Gemcitabine resistance in breast cancer cells regulated by PI3K/AKT-mediated cellular proliferation exerts negative feedback via the MEK/MAPK and mTOR pathways

DEPTOR Is a Stemness Factor That Regulates Pluripotency of Embryonic Stem Cells

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