Stimulation of Vascular Endothelial Growth Factor Gene Transcription by all trans Retinoic Acid through Sp1 and Sp3 Sites in Human Bronchioloalveolar Carcinoma Cells
- 1 February 2002
- journal article
- Published by American Thoracic Society in American Journal of Respiratory Cell and Molecular Biology
- Vol. 26 (2), 246-253
- https://doi.org/10.1165/ajrcmb.26.2.4509
Abstract
In this study, we examined the effects of all trans-retinoic acid (at-RA) on the vascular endothelial growth factor (VEGF) expression in human bronchioloalveolar carcinoma NCI-H322 cells to evaluate the potential of at-RA to affect tumor progression. Northern blot and enzyme-linked immunosorbent assay analyses indicate that VEGF production is significantly increased by 1 μ M of at-RA. A series of 5 ′ -deletion and site-directed mutation analyses indicated that G + C-rich sequence located at − 81 and − 52 was required for at-RA– and retinoic acid receptor α –mediated induction of VEGF promoter. Electrophoretic mobility shift and supershift assays showed that major constituents of nuclear factors binding to G + C-rich sequences are Sp1 and Sp3. Pretreatment with cycloheximide, a protein synthesis inhibitor, prevented the at-RA–mediated induction of VEGF mRNA expression. Likewise, at-RA–mediated VEGF expression was completely blocked in the presence of genistein, an inhibitor for tyrosine kinases. These results suggest that an increase in transcription of the VEGF promoter by at-RA is mediated through Sp1 site, and both new protein synthesis and tyrosine kinase activation are necessary for this induction. Because VEGF can promote neovascularization in cancer cells, an induction of VEGF by at-RA may preclude the therapeutic application of at-RA to cancer patients.Keywords
This publication has 30 references indexed in Scilit:
- The induction and activation of STAT1 by all-trans-retinoic acid are mediated by RARβ signaling pathways in breast cancer cellsOncogene, 1999
- All-trans-retinoic Acid Increases Transforming Growth Factor-β2 and Insulin-like Growth Factor Binding Protein-3 Expression through a Retinoic Acid Receptor-α-dependent Signaling PathwayPublished by Elsevier BV ,1997
- Synergistic induction of endothelial tissue factor by tumor necrosis factor and vascular endothelial growth factor: functional analysis of the tumor necrosis factor receptorsFEBS Letters, 1996
- The Mouse Gene for Vascular Endothelial Growth FactorPublished by Elsevier BV ,1996
- Interleukin 6 Induces the Expression of Vascular Endothelial Growth FactorJournal of Biological Chemistry, 1996
- Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivoNature, 1993
- Vascular endothelial growth factor (VEGF) induces plasminogen activators and plasminogen activator inhibitor-1 in microvascular endothelial cellsBiochemical and Biophysical Research Communications, 1991
- Vascular Endothelial Growth Factor Is a Secreted Angiogenic MitogenScience, 1989
- Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cellsBiochemical and Biophysical Research Communications, 1989
- EFFECT OF EETINOIC ACID IN PSORIASISBritish Journal of Dermatology, 1970