Publication details

Hypoxia Downregulates MAPK/ERK but Not STAT3 Signaling in ROS-Dependent and HIF-1-Independent Manners in Mouse Embryonic Stem Cells

Authors

KUČERA Jan NETUŠILOVÁ Julie SLADEČEK Stanislava KOHUTKOVÁ LÁNOVÁ Martina VAŠÍČEK Ondřej ŠTEFKOVÁ Kateřina NAVRÁTILOVÁ J. KUBALA Lukáš PACHERNÍK Jiří

Year of publication 2017
Type Article in Periodical
Magazine / Source Oxidative Medicine and Cellular Longevity
MU Faculty or unit

Faculty of Science

Citation
Doi http://dx.doi.org/10.1155/2017/4386947
Keywords PROTEIN PHOSPHATASE 2A; CHLORIDE-INDUCED APOPTOSIS; INDUCIBLE FACTOR 1-ALPHA; MAP KINASE; SELF-RENEWAL; HIF-1-ALPHA ACCUMULATION; UNDIFFERENTIATED STATE; TYROSINE-PHOSPHATASE; REDOX-REGULATION; IRON CHELATOR
Description Hypoxia is involved in the regulation of stem cell fate, and hypoxia-inducible factor 1 (HIF-1) is the master regulator of hypoxic response. Here, we focus on the effect of hypoxia on intracellular signaling pathways responsible for mouse embryonic stem (ES) cell maintenance. We employed wild-type and HIF-1 alpha-deficient ES cells to investigate hypoxic response in the ERK, Akt, and STAT3 pathways. Cultivation in 1% O-2 for 24 h resulted in the strong dephosphorylation of ERK and its upstream kinases and to a lesser extent of Akt in an HIF-1-independent manner, while STAT3 phosphorylation remained unaffected. Downregulation of ERK could not be mimicked either by pharmacologically induced hypoxia or by the overexpression. Dual-specificity phosphatases (DUSP) 1, 5, and 6 are hypoxia-sensitive MAPK-specific phosphatases involved in ERK downregulation, and protein phosphatase 2A (PP2A) regulates both ERK and Akt. However, combining multiple approaches, we revealed the limited significance of DUSPs and PP2A in the hypoxia-mediated attenuation of ERK signaling. Interestingly, we observed a decreased reactive oxygen species (ROS) level in hypoxia and a similar phosphorylation pattern for ERK when the cells were supplemented with glutathione. Therefore, we suggest a potential role for the ROS-dependent attenuation of ERK signaling in hypoxia, without the involvement of HIF-1.