Regulation of Vascular Endothelial Growth Factor D by Orphan Receptors Hepatocyte Nuclear Factor-4α and Chicken Ovalbumin Upstream Promoter Transcription Factors 1 and 2
| Autor: | Johannes Hertel, Michael Höcker, Christoph Wissmann, Georgia Schäfer, Victoria Lunyak |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Cancer Research
Molecular Sequence Data Response element Chicken ovalbumin upstream promoter-transcription factor Vascular Endothelial Growth Factor D Biology Transfection COUP Transcription Factor II Histones Nuclear Receptor Coactivator 2 Transactivation Sp3 transcription factor Tumor Cells Cultured medicine Humans Promoter Regions Genetic Transcription factor Histone Acetyltransferases COUP Transcription Factor I Base Sequence Acetylation Promoter CREB-Binding Protein Molecular biology Trichostatin A Gene Expression Regulation Hepatocyte Nuclear Factor 4 Oncology TAF2 Trans-Activators Protein Binding medicine.drug |
| Zdroj: | Cancer Research. 68:457-466 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-07-5136 |
| Popis: | Vascular endothelial growth factor D has recently been linked to the control of lymphangiogenesis and lymphatic metastasis. The molecular determinants regulating vegf-D gene transcription, however, have not yet been identified. After isolation of 2 kb of 5′-flanking DNA of the human vegf-D gene, we identified a novel, atypical direct repeat (DR) element consisting of a consensus half-site (AGGTCA) at −125/−119 and a degenerated DR half-site (ATGTTA) at −99/−94 as sufficient and necessary for vegf-D transcription. The vegf-D DR element is bound and activated by the orphan receptors hepatocyte nuclear factor 4α (HNF-4α) and chicken ovalbumin upstream promoter transcription factor (COUP-TF)-1/COUP-TF2. Additionally, chromatin immunoprecipitation assays identified transcriptional coactivators cyclic AMP–responsive element binding protein–binding protein and glucocorticoid receptor interacting protein 1 at the vegf-D DR element and functional assays confirmed their stimulatory effect on the vegf-D promoter. Histone deacetylase inhibition by trichostatin A led to accumulation of acetylated histones H3/H4 at the vegf-D promoter, up-regulation of vegf-D mRNA levels, and transactivation of vegf-D promoter reporter gene constructs in cancer cell lines. This study for the first time describes the molecular determinants in cis and trans controlling vegf-D gene transcription and identifies interaction of HNF-4α and COUP-TF1/COUP-TF2 with a proximal, atypical DR element as indispensable for vegf-D transcription. Moreover, our findings suggest that epigenetic control of histone acetylation represents an important determinant of vegf-D gene expression in cancer cells. These results provide novel insights into the molecular machinery controlling vegf-D gene expression and may add to a better understanding of the regulation of lymphangiogenesis in vascular development and cancer. [Cancer Res 2008;68(2):457–66] |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|