Signaling by the receptor for stein cell factor (SCIF). 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 ate 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-1 alpha and HIF-2 alpha protein accumulation at normoxia. In addition, SCF-induced HIF-1 alpha was transcriptionally active, and transcribed HIF-1 target genes such as VEGF, BNIP3, GLUT1 and DEC1, all effect that could be reversed by siRNA against HIF-1 x We also show that SCF-induced accumulation of HIF-1 alpha is dependent oil 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. (C) 2008 Elsevier Inc. All rights reserved.