Both Hypoxia-Inducible Factor 1 and MAPK Signaling Pathway Attenuate PI3K/AKT via Suppression of ...

@article{1774717,
   author = {Fojtík, Petr and Beckerová, Deborah and Holomková, Kateřina and Šenfluk, Martin and Rotrekl, Vladimír},
   article_location = {Lausanne},
   article_number = {JAN 2021},
   doi = {http://dx.doi.org/10.3389/fcell.2020.607444},
   keywords = {PI3K; AKT; MAPK; reactive oxygen species; hPSCs; HIF-1; hypoxia},
   language = {eng},
   issn = {2296-634X},
   journal = {Frontiers in Cell and Developmental Biology},
   title = {Both Hypoxia-Inducible Factor 1 and MAPK Signaling Pathway Attenuate PI3K/AKT via Suppression of Reactive Oxygen Species in Human Pluripotent Stem Cells},
   url = {https://www.frontiersin.org/articles/10.3389/fcell.2020.607444/full},
   volume = {8},
   year = {2021}
}

TY  - JOUR
ID  - 1774717
AU  - Fojtík, Petr - Beckerová, Deborah - Holomková, Kateřina - Šenfluk, Martin - Rotrekl, Vladimír
PY  - 2021
TI  - Both Hypoxia-Inducible Factor 1 and MAPK Signaling Pathway Attenuate PI3K/AKT via Suppression of Reactive Oxygen Species in Human Pluripotent Stem Cells
JF  - Frontiers in Cell and Developmental Biology
VL  - 8
IS  - JAN 2021
SP  - 1-18
EP  - 1-18
PB  - Frontiers Media S.A.
SN  - 2296634X
KW  - PI3K
KW  - AKT
KW  - MAPK
KW  - reactive oxygen species
KW  - hPSCs
KW  - HIF-1
KW  - hypoxia
UR  - https://www.frontiersin.org/articles/10.3389/fcell.2020.607444/full
N2  - Mild hypoxia (5% O-2) as well as FGFR1-induced activation of phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B (PI3K/AKT) and MAPK signaling pathways markedly support pluripotency in human pluripotent stem cells (hPSCs). This study demonstrates that the pluripotency-promoting PI3K/AKT signaling pathway is surprisingly attenuated in mild hypoxia compared to the 21% O-2 environment. Hypoxia is known to be associated with lower levels of reactive oxygen species (ROS), which are recognized as intracellular second messengers capable of upregulating the PI3K/AKT signaling pathway. Our data denote that ROS downregulation results in pluripotency upregulation and PI3K/AKT attenuation in a hypoxia-inducible factor 1 (HIF-1)-dependent manner in hPSCs. Using specific MAPK inhibitors, we show that the MAPK pathway also downregulates ROS and therefore attenuates the PI3K/AKT signaling-this represents a novel interaction between these signaling pathways. This inhibition of ROS initiated by MEK1/2-ERK1/2 may serve as a negative feedback loop from the MAPK pathway toward FGFR1 and PI3K/AKT activation. We further describe the molecular mechanism resulting in PI3K/AKT upregulation in hPSCs-ROS inhibit the PI3K's primary antagonist PTEN and upregulate FGFR1 phosphorylation. These novel regulatory circuits utilizing ROS as second messengers may contribute to the development of enhanced cultivation and differentiation protocols for hPSCs. Since the PI3K/AKT pathway often undergoes an oncogenic transformation, our data could also provide new insights into the regulation of cancer stem cell signaling.
ER  - 

FOJTÍK, Petr, Deborah BECKEROVÁ, Kateřina HOLOMKOVÁ, Martin ŠENFLUK and Vladimír ROTREKL. Both Hypoxia-Inducible Factor 1 and MAPK Signaling Pathway Attenuate PI3K/AKT via Suppression of Reactive Oxygen Species in Human Pluripotent Stem Cells. \textit{Frontiers in Cell and Developmental Biology}. Lausanne: Frontiers Media S.A., 2021, vol.~8, JAN 2021, p.~1-18. ISSN~2296-634X. Available from: https://dx.doi.org/10.3389/fcell.2020.607444.