| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Binó, Lucia Kucera, Jan Stefková, Katerina Svihálková Sindlerová, Lenka Lánová, Martina Kudová, Jana Kubala, Lukás Pacherník, Jirí |
| Description |
Author Affiliation: Binó L ( Institute of Biophysics, Academy of Sciences of the Czech Republic v. v. i., Královopolská 135, 612 65 Brno, Czech Republic); Kucera J ( Institute of Experimental Biology, Department of Physiology and Immunology of Animals, Faculty of Science, Masaryk University, Kotlárská 2, 611 37 Brno, Czech Republic.); Stefková K ( Institute of Experimental Biology, Department of Physiology and Immunology of Animals, Faculty of Science, Masaryk University, Kotlárská 2, 611 37 Brno, Czech Republic.); Svihálková Sindlerová L ( Institute of Biophysics, Academy of Sciences of the Czech Republic v. v. i., Královopolská 135, 612 65 Brno, Czech Republic); Lánová M ( Institute of Experimental Biology, Department of Physiology and Immunology of Animals, Faculty of Science, Masaryk University, Kotlárská 2, 611 37 Brno, Czech Republic.); Kudová J ( Institute of Biophysics, Academy of Sciences of the Czech Republic v. v. i., Královopolská 135, 612 65 Brno, Czech Republic); Kubala L ( Institute of Biophysics, Academy of Sciences of the Czech Republic v. v. i., Královopolská 135, 612 65 Brno, Czech Republic); Pacherník J ( Institute of Experimental Biology, Department of Physiology and Immunology of Animals, Faculty of Science, Masaryk University, Kotlárská 2, 611 37 Brno, Czech Republic) |
| Abstract |
Hypoxic conditions are suggested to affect the differentiation status of stem cells (SC), including embryonic stem cells (ESC). Hypoxia inducible factor (HIF) is one of the main intracellular molecules responsible for the cellular response to hypoxia. Hypoxia stabilizes HIF by inhibiting the activity of HIF prolyl-hydroxylases (PHD), which are responsible for targeting HIF-alpha subunits for proteosomal degradation. To address the impact of HIF stabilization on the maintenance of the stemness signature of mouse ESC (mESC), we tested the influence of the inhibition of PHDs and hypoxia (1% O2 and 5% O2) on spontaneous ESC differentiation triggered by leukemia inhibitory factor withdrawal for 24 and 48 h. The widely used panhydroxylase inhibitor dimethyloxaloylglycine (DMOG) and PHD inhibitor JNJ-42041935 (JNJ) with suggested higher specificity towards PHDs were employed. Both inhibitors and both levels of hypoxia significantly increased HIF-1alpha and HIF-2alpha protein levels and HIF transcriptional activity in spontaneously differentiating mESC. This was accompanied by significant downregulation of cell proliferation manifested by the complete inhibition of DNA synthesis and partial arrest in the S phase after 48 h. Further, HIF stabilization enhanced downregulation of the expressions of some pluripotency markers (OCT-4, NANOG, ZFP-42, TNAP) in spontaneously differentiating mESC. However, at the same time, there was also a significant decrease in the expression of some genes selected as markers of cell differentiation (e.g. SOX1, BRACH T, ELF5). In conclusion, the short term stabilization of HIF mediated by the PHD inhibitors JNJ and DMOG and hypoxia did not prevent the spontaneous loss of pluripotency markers in mESC. However, it significantly downregulated the proliferation of these cells. |
| File Format |
HTM / HTML |
| ISSN |
00092797 |
| Volume Number |
244 |
| e-ISSN |
18727786 |
| Journal |
Chemico-Biological Interactions |
| Language |
English |
| Publisher |
Elsevier |
| Publisher Date |
2016-01-25 |
| Publisher Place |
Ireland |
| Access Restriction |
One Nation One Subscription (ONOS) |
| Subject Keyword |
Discipline Biochemistry Discipline Pharmacology Cell Differentiation Drug Effects Enzyme Inhibitors Pharmacology Hypoxia-inducible Factor 1 Metabolism Mouse Embryonic Stem Cells Cytology Amino Acids, Dicarboxylic Chemistry Animals Benzimidazoles Cell Cycle Cell Proliferation Cell Survival Cells, Cultured Dose-response Relationship, Drug Anoxia Hypoxia-inducible Factor-proline Dioxygenases Antagonists & Inhibitors Mice Protein Stability Pyrazoles Structure-activity Relationship Journal Article Research Support, Non-u.s. Gov't |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Medicine Toxicology |
