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.
Highlights
Stem cell factor (SCF) is a cytokine that plays a crucial role in hematopoiesis and melanogenesis [1]
Since SCF acts via MEK, PI3 kinase and possibly protein kinase C (PKC) a/b isoforms [5,7], one could hypothesise that SCF as such impacts on the activation of NADPH oxidase leading to the generation of reactive oxygen species (ROS) [6]
SCF is recognised as a hematopoietic growth factor that exerts its activity by signalling through the type III receptor tyrosine kinase known as Kit receptor or CD117 [1]
Summary
Stem cell factor (SCF) is a cytokine that plays a crucial role in hematopoiesis and melanogenesis [1]. It is recognised by the Kit receptor, known as CD117 [1,2], which is expressed in different types of non-differentiated hematopoietic cells including myeloblasts and pro-monoblasts [1]. HIF-1 is a heterodimeric protein containing a constitutive beta and an inducible alpha subunit. This complex plays a pivotal role in cellular adaptation to low oxygen availability as well as to the inflammatory stress associated with innate immune responses or allergic reactions [6]. It has been reported that mitogen-activated protein (MAP) and extracellular signal-regulating kinase (ERK) kinase (MEK) as well as phosphoinositide 3-kinase (PI3 kinase) but not p38 MAP kinase, play a role in SCF-induced HIF-1a accumulation in human myeloid leukaemia cells [5]
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