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- Franklin, Gary C., et al.
(författare)
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An Inr-containing sequence flanking the TATA box of the human c-sis (PDGF-B) proto-oncogene promoter functions in cis as a co-activator for its intronic enhancer
- 1995
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Ingår i: Oncogene. - 0950-9232 .- 1476-5594. ; 11:9, s. 1873-1884
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- High-level activity of the human PDGF-B promoter in choriocarcinoma cell lines depends upon an atypical, intronic enhancer-like element which does not function with heterologous promoters tested. An extensive series of mutant PDGF-B promoter-driven constructs identified a sequence flanking the TATA box which is required specifically for enhancer-mediated transcription in human choriocarcinoma cell lines. This element, which we here term an enhancer-dependent cis co-activator (EDC) contains an Inr (initiator) consensus sequence upstream of the TATA box which is required, but not sufficient for its function. Requirement for the EDC is cell type-specific, since it was dispensable for enhancer-mediated transcription in a human breast cancer cell line. Although it lies within the region defined, the TATA box itself is not required for EDC function, or for basal promoter function which may derive from a second Inr-like sequence situated at the transcriptional start site. These observations indicate that interactions between some promoter and enhancer elements may be more complex than that generally described for 'classical' enhancer systems and may suggest an additional function for the initiator motif.
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| 2. |
- Miller, Stephen J.
(författare)
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Transcriptional regulation of the platelet-derived growth factor B gene
- 1998
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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