Stem cell factor induces HIF-1alpha at normoxia in hematopoietic cells.
Signaling by the receptor for stem cell factor (SCF), c-Kit, is of major importance for hematopoiesis, melanogenesis and reproduction, and the biological responses are commonly proliferation and cell survival. Thus, constitutive activation due to c-Kit mutations is involved in the pathogenesis of several forms of cancer, e.g. leukemias, gastrointestinal stromal tumors and testicular tumors. Tumor survival requires oxygen supply through induced neovascularization, a process largely mediated by the vascular endothelial growth factor (VEGF), a prominent target of the transcription factors hypoxia-inducible factor-1 (HIF-1) and HIF-2. Using Affymetrix microarrays we have identified genes that are upregulated following SCF stimulation. Interestingly, many of the genes induced were found to be related to a hypoxic response. These findings were corroborated by our observation that SCF stimulation of the hematopoietic cell lines M-07e induces HIF-1alpha and HIF-2alpha protein accumulation at normoxia. In addition, SCF-induced HIF-1alpha was transcriptionally active, and transcribed HIF-1 target genes such as VEGF, BNIP3, GLUT1 and DEC1, an effect that could be reversed by siRNA against HIF-1alpha. We also show that SCF-induced accumulation of HIF-1alpha is dependent on both the PI-3-kinase and Ras/MEK/Erk pathways. Our data suggest a novel mechanism of SCF/c-Kit signaling in angiogenesis and tumor progression.
Department of Laboratory Medicine, Lund University, Malmö University Hospital, Malmö, Sweden.
Malin
M
Pedersen
Tobias
T
Löfstedt
Jianmin
J
Sun
Linda
L
Holmquist-Mengelbier
Sven
S
Påhlman
Lars
L
Rönnstrand
D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D009369:Neoplasms / Q000098:blood supply / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D018919:Neovascularization, Physiologic; D010100:Oxygen / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019089:Stem Cell Factor / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D018631:ras Proteins / Q000378:metabolism
D048049:Extracellular Signal-Regulated MAP Kinases; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020930:MAP Kinase Kinase Kinases; D008565:Membrane Proteins; D010100:Oxygen; D019869:Phosphatidylinositol 3-Kinases; D011518:Proto-Oncogene Proteins; D019089:Stem Cell Factor; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; D018631:ras Proteins; C090121:BNIP3 protein, human; C403671:DELEC1 protein, human; C497442:HIF1A protein, human; C467484:VEGFA protein, human