Stem cell factor induces HIF-1alpha at normoxia in hematopoietic cells.
Författare
Summary, in English
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.
Publiceringsår
2008
Språk
Engelska
Sidor
98-103
Publikation/Tidskrift/Serie
Biochemical and Biophysical Research Communications
Volym
98
Issue
103
Länkar
Dokumenttyp
Artikel i tidskrift
Förlag
Elsevier
Ämne
- Biological Sciences
Nyckelord
- Receptor
- tyrosine kinase
- Hypoxia
- HIF-1 alpha
- Affymetrix
- Stem cell factor
- c-Kit
Status
Published
ISBN/ISSN/Övrigt
- ISSN: 1090-2104