Transcriptional regulation of the platelet-derived growth factor B gene

Sammanfattning: The Platelet-Derived Growth Factor B (PDGF-B) gene product is an important protein during development and adult life, as well as being associated with the development of many tumour types. It has been ascribed roles in many normal and pathological processes including angiogenesis, tissue repair, atherosclerosis and cytotrophoblast proliferation.The transcriptional regulation of the PDGF-B gene is very complex and multiple levels of regulation have been demonstrated. A full understanding of how levels of this biologically important molecule are controlled may allow therapeutic control of this gene. The control of the expression of PDGF-B in choriocarcinoma cells (JEG-3) was shown to involve a unique promoter-specific enhancer. The PDGF-B promoter was characterised and an element within the promoter was shown to control its specific interaction with the enhancer. The enhancer was subsequently characterised and was shown to be composed of two independent elements. One of these elements was shown to be responsible for the interaction of the enhancer with the promoter, while the other was shown to be responsible for the activation by the enhancer. The activation element failed to independently activate the PDGF-B promoter at a distance without the cooperation of the second element. We propose the possibility that many "proximal-only" elements may be directed to work via promoters in this fashion.During development and tumourigenesis, there will be times that cells/tissues are deprived of oxygen (hypoxia) and to survive, they need to take measures to overcome this deprivation. PDGF-B has previously been reported to be up-regulated by hypoxia in endothelial cells. In contrast, however, we show a down-regulation of PDGF-B and suggest a link between prehypoxia levels of PDGF-B and the response to hypoxia.Much emphasis has centred on the effect of histone acetylation on gene transcription. The effect of acetylation on endogenous PDGF-B expression and on the promoter/enhancer system we have described, was examined in multiple cell-types.