The stabilization of hypoxia inducible factor modulates
differentiation status and inhibits the proliferation of mouse
embryonic stem cells

J 2016

The stabilization of hypoxia inducible factor modulates differentiation status and inhibits the proliferation of mouse embryonic stem cells

BINÓ, Lucia, Jan KUČERA, Kateřina ŠTEFKOVÁ, Lenka ŠVIHÁLKOVÁ ŠINDLEROVÁ, Martina LÁNOVÁ et. al.

Základní údaje

Originální název

The stabilization of hypoxia inducible factor modulates differentiation status and inhibits the proliferation of mouse embryonic stem cells

Autoři

BINÓ, Lucia (703 Slovensko, domácí), Jan KUČERA (203 Česká republika, domácí), Kateřina ŠTEFKOVÁ (203 Česká republika, domácí), Lenka ŠVIHÁLKOVÁ ŠINDLEROVÁ (203 Česká republika), Martina LÁNOVÁ (203 Česká republika, domácí), Jana KUDOVÁ (203 Česká republika, domácí), Lukáš KUBALA (203 Česká republika, garant) a Jiří PACHERNÍK (203 Česká republika, domácí)

Vydání

Chemico-Biological Interactions, Clare, Elsevier Ireland Ltd. 2016, 0009-2797

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

Genetika a molekulární biologie

Stát vydavatele

Irsko

Utajení

není předmětem státního či obchodního tajemství

Impakt faktor

Impact factor: 3.143

Kód RIV

RIV/00216224:14310/16:00089311

Organizační jednotka

Přírodovědecká fakulta

DOI

http://dx.doi.org/10.1016/j.cbi.2015.12.007

UT WoS

000369152000022

Klíčová slova anglicky

DMOG; Embryonic stem cells; HIF-1; Hypoxia; JNJ-42041935; Prolyl hydroxylase

Štítky

AKR, EL OK, podil, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 14. 4. 2017 15:40, Ing. Andrea Mikešková

Anotace

V originále

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.

Citovat

BINÓ, Lucia, Jan KUČERA, Kateřina ŠTEFKOVÁ, Lenka ŠVIHÁLKOVÁ ŠINDLEROVÁ, Martina LÁNOVÁ, Jana KUDOVÁ, Lukáš KUBALA a Jiří PACHERNÍK. The stabilization of hypoxia inducible factor modulates differentiation status and inhibits the proliferation of mouse embryonic stem cells. Chemico-Biological Interactions. Clare: Elsevier Ireland Ltd., 2016, roč. 244, January, s. 204-214. ISSN 0009-2797. Dostupné z: https://dx.doi.org/10.1016/j.cbi.2015.12.007.

@article{1333046,
   author = {Binó, Lucia and Kučera, Jan and Štefková, Kateřina and Švihálková Šindlerová, Lenka and Lánová, Martina and Kudová, Jana and Kubala, Lukáš and Pacherník, Jiří},
   article_location = {Clare},
   article_number = {January},
   doi = {http://dx.doi.org/10.1016/j.cbi.2015.12.007},
   keywords = {DMOG; Embryonic stem cells; HIF-1; Hypoxia; JNJ-42041935; Prolyl hydroxylase},
   language = {eng},
   issn = {0009-2797},
   journal = {Chemico-Biological Interactions},
   title = {The stabilization of hypoxia inducible factor modulates differentiation status and inhibits the proliferation of mouse embryonic stem cells},
   volume = {244},
   year = {2016}
}

TY  - JOUR
ID  - 1333046
AU  - Binó, Lucia - Kučera, Jan - Štefková, Kateřina - Švihálková Šindlerová, Lenka - Lánová, Martina - Kudová, Jana - Kubala, Lukáš - Pacherník, Jiří
PY  - 2016
TI  - The stabilization of hypoxia inducible factor modulates differentiation status and inhibits the proliferation of mouse embryonic stem cells
JF  - Chemico-Biological Interactions
VL  - 244
IS  - January
SP  - 204-214
EP  - 204-214
PB  - Elsevier Ireland Ltd.
SN  - 00092797
KW  - DMOG
KW  - Embryonic stem cells
KW  - HIF-1
KW  - Hypoxia
KW  - JNJ-42041935
KW  - Prolyl hydroxylase
N2  - 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.
ER  -

BINÓ, Lucia, Jan KUČERA, Kateřina ŠTEFKOVÁ, Lenka ŠVIHÁLKOVÁ ŠINDLEROVÁ, Martina LÁNOVÁ, Jana KUDOVÁ, Lukáš KUBALA a Jiří PACHERNÍK. The stabilization of hypoxia inducible factor modulates differentiation status and inhibits the proliferation of mouse embryonic stem cells. \textit{Chemico-Biological Interactions}. Clare: Elsevier Ireland Ltd., 2016, roč.~244, January, s.~204-214. ISSN~0009-2797. Dostupné z: https://dx.doi.org/10.1016/j.cbi.2015.12.007.

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