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Hypoxia-inducible factor-1 alpha inhibits self-renewal of mouse embryonic stem cells in Vitro via negative regulation of the leukemia inhibitory factor-STAT3 pathway
Cited 75 time in
Web of Science
Cited 79 time in Scopus
- Authors
- Issue Date
- 2007-03-16
- Citation
- J Biol Chem. 2007 May 4;282(18):13672-9. Epub 2007 Mar 14.
- Keywords
- Animals ; Cell Differentiation/drug effects/*physiology ; Cell Hypoxia/physiology ; Cell Proliferation/drug effects ; Embryonic Development/physiology ; Embryonic Stem Cells/cytology/*metabolism ; Gene Expression Regulation, Developmental/drug effects/physiology ; Hypoxia-Inducible Factor 1, alpha ; Subunit/genetics/*metabolism/pharmacology ; Leukemia Inhibitory Factor/genetics/*metabolism ; Mice ; RNA, Small Interfering/genetics ; Receptors, OSM-LIF/genetics/metabolism ; Response Elements/physiology ; STAT3 Transcription Factor/genetics/*metabolism ; Signal Transduction/drug effects/*physiology
- Abstract
- During mammalian embryogenesis, the early embryo grows in a relatively hypoxic environment due to a restricted supply of oxygen. The molecular mechanisms underlying modulation of self-renewal and differentiation of mouse embryonic stem cells (mESCs) under such hypoxic conditions remain to be established. Here, we show that hypoxia inhibits mESC self-renewal and induces early differentiation in vitro, even in the presence of leukemia inhibitory factor (LIF). These effects are mediated by down-regulation of the LIF-STAT3 signaling pathway. Under conditions of hypoxia, hypoxia-inducible factor-1alpha (HIF-1alpha) suppresses transcription of LIF-specific receptor (LIFR) by directly binding to the reverse hypoxia-responsive element located in the LIFR promoter. Ectopic expression and small interference RNA knockdown of HIF-1alpha verified the inhibitory effect on LIFR transcription. Our findings collectively suggest that hypoxia-induced in vitro differentiation of mESCs is triggered, at least in part, by the HIF-1alpha-mediated suppression of LIF-STAT3 signaling.
- ISSN
- 0021-9258 (Print)
- Language
- English
- URI
- http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17360716
https://hdl.handle.net/10371/15960
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