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In vitro study of HIF-1 activation and VEGF release by bFGF in the T47D breast cancer cell line under normoxic conditions: involvement of PI-3K/Akt and MEK1/ERK pathways
- Source :
- The Journal of Pathology. 205:530-536
- Publication Year :
- 2005
- Publisher :
- Wiley, 2005.
-
Abstract
- Hypoxia-inducible factor (HIF) is critical in the modulation of tumour angiogenesis in response to hypoxia. In the present study, the mechanisms underlying basic fibroblast growth factor (bFGF)-induced activation of HIF-1 and the subsequent release of vascular endothelial growth factor (VEGF) in a human breast cancer cell line (T47D) under normoxic conditions were explored. The data show that HIF-1α expression is induced by bFGF in a dose- and time-dependent fashion, while increased HIF-1α protein expression and transactivity of HIF-1 are due to the phosphorylation of Akt by bFGF, as indicated by application of the phosphatidylinositol 3-kinase (PI-3K) inhibitor LY294002. The data also show that the MEK1 (mitogen-activated protein kinase kinase-1)/ERK (extracellular signal-regulated kinase) pathway is only involved in bFGF-induced transactivity of HIF-1, but not HIF-1α expression, indicating roles for both the PI-3K/Akt and the MEK1/ERK pathways in bFGF activity. In addition, the translation inhibitor cycloheximide confirmed that bFGF-induced HIF-1α protein expression was due to de novo protein synthesis. In contrast, p38 was not required for the expression of HIF-1α or HIF-1 transactivity, although significant phosphorylation of p38 was observed after bFGF treatment. Treatment of the cells with bFGF increased the amount of VEGF release, and this could be suppressed by either PD98059 or LY294002, suggesting the presence of a HIF-1α-dependent pathway for bFGF-induced VEGF production. In conclusion, the PI-3K/Akt and MEK1/ERK pathways, in a potentially independent and co-operative fashion, can modulate HIF-1 activation by bFGF. Further studies will pinpoint whether HIF-1 is the transcriptional factor responsible for the increased VEGF production following bFGF treatment of breast tumour cells. Copyright © 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
- Subjects :
- Vascular Endothelial Growth Factor A
MAPK/ERK pathway
medicine.medical_specialty
Angiogenesis
Morpholines
p38 mitogen-activated protein kinases
Basic fibroblast growth factor
MAP Kinase Kinase 1
Breast Neoplasms
Protein Serine-Threonine Kinases
Biology
p38 Mitogen-Activated Protein Kinases
Pathology and Forensic Medicine
Phosphatidylinositol 3-Kinases
chemistry.chemical_compound
Cell Line, Tumor
Proto-Oncogene Proteins
Internal medicine
medicine
Humans
Cycloheximide
Enzyme Inhibitors
Phosphorylation
Protein kinase A
Protein kinase B
Protein Synthesis Inhibitors
Kinase
Nuclear Proteins
Hypoxia-Inducible Factor 1, alpha Subunit
DNA-Binding Proteins
Vascular endothelial growth factor
Endocrinology
chemistry
Chromones
Cancer research
Female
Fibroblast Growth Factor 2
Hypoxia-Inducible Factor 1
Proto-Oncogene Proteins c-akt
Signal Transduction
Transcription Factors
Subjects
Details
- ISSN :
- 10969896 and 00223417
- Volume :
- 205
- Database :
- OpenAIRE
- Journal :
- The Journal of Pathology
- Accession number :
- edsair.doi.dedup.....aa7a8ae2b2f46efd952ec5109e40d3b4