title: Effects of stem cell factor on hypoxia-inducible factor 1 alpha accumulation in human acute myeloid leukaemia and LAD2 mast cells.
abstract: Stem cell factor (SCF) is a hematopoietic growth factor that exerts its activity by signalling through the tyrosine kinase receptor known as Kit or CD117. SCF-Kit signalling is crucial for the survival, proliferation and differentiation of hematopoietic cells of myeloid lineage. Furthermore, since myeloid leukaemia cells express the Kit receptor, SCF may play an important role in myeloid leukaemia progression too. However, the mechanisms of this pathophysiological effect remain unclear. Recent evidence shows that SCF triggers accumulation of the inducible alpha subunit of hypoxia-inducible factor 1 (HIF-1) in hematopoietic cells--a transcription complex that plays a pivotal role in cellular adaptation to low oxygen availability. However, it is unknown how SCF impacts on HIF-1α accumulation in human myeloid leukaemia and mast cells. Here we show that SCF induces HIF-1α accumulation in THP-1 human myeloid leukaemia cells but not in LAD2 mast cells. We demonstrated that LAD2 cells have a more robust glutathione (GSH)-dependent antioxidative system compared to THP-1 cells and are therefore protected against the actions of ROS generated in an SCF-dependent manner. BSO-induced GSH depletion led to a significant decrease in HIF-1α prolyl hydroxylase (PHD) activity in THP-1 cells and to near attenuation of it in LAD2 cells. In THP-1 cells, SCF-induced HIF-1α accumulation is controlled via ERK, PI3 kinase/PKC-δ/mTOR-dependent and to a certain extent by redox-dependent mechanisms. These results demonstrate for the first time an important cross-talk of signalling pathways associated with HIF-1 activation--an important stage of the myeloid leukaemia cell life cycle.
authors.affiliation: Medway School of Pharmacy, University of Kent, Kent, United Kingdom. B.F.Gibbs@kent.ac.uk
authors.forename: Bernhard F
authors.initials: BF
authors.lastname: Gibbs
authors.forename: Inna M
authors.initials: IM
authors.lastname: Yasinska
authors.forename: Abraham E
authors.initials: AE
authors.lastname: Oniku
authors.forename: Vadim V
authors.initials: VV
authors.lastname: Sumbayev
mesh_terms: D000595:Amino Acid Sequence; D000975:Antioxidants / Q000378:metabolism; D045744:Cell Line, Tumor; D049308:Dioxygenases / Q000378:metabolism; D005978:Glutathione / Q000172:deficiency / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000737:chemistry / Q000378:metabolism*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D015470:Leukemia, Myeloid, Acute / Q000276:immunology / Q000378:metabolism*; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism*; D008969:Molecular Sequence Data; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019089:Stem Cell Factor / Q000494:pharmacology*; D013858:Thiobarbiturates / Q000378:metabolism
chemical_list: D000975:Antioxidants; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019089:Stem Cell Factor; D013858:Thiobarbiturates; D049308:Dioxygenases; C488894:EGLN3 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D005978:Glutathione; C029684:thiobarbituric acid