Abstract
The EWS/ETS fusion proteins associated with Ewings family tumors (EFTs) are thought to promote oncogenesis by acting as aberrant transcription factors. Uridine phosphorylase is a gene that is up-regulated by structurally distinct EWS/ETS fusions. Ectopic expression of uridine phosphorylase was able to support anchorage-independent cell growth, indicating that it plays an active role in the oncogenic process. Transcriptional up-regulation of uridine phosphorylase is shown to be mediated in a DNA binding-dependent manner, and reporter gene assays demonstrated that EWS/FLI1 and RAS mediate activation through a single activator protein 1/ETS site located in the uridine phosphorylase promoter. Chromatin immunoprecipitation assays reveal that EWS/FLI1 directly associates with the uridine phosphorylase promoter in vivo. Up-regulation of uridine phosphorylase by EWS/FLI1 sensitizes cells to growth inhibition by the pyrimidine analogue, 5'-deoxy-5'fluorouridine, both in tissue culture and in vivo model systems.
Publication types
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
3T3 Cells
-
Animals
-
DNA / metabolism
-
Floxuridine / pharmacology
-
Humans
-
Mice
-
Oncogene Proteins, Fusion / biosynthesis
-
Oncogene Proteins, Fusion / genetics
-
Oncogene Proteins, Fusion / physiology
-
Promoter Regions, Genetic
-
Protein Structure, Tertiary
-
Proto-Oncogene Protein c-fli-1
-
Proto-Oncogene Proteins / biosynthesis
-
Proto-Oncogene Proteins / genetics
-
Proto-Oncogene Proteins / physiology*
-
Proto-Oncogene Proteins c-ets
-
RNA-Binding Protein EWS / biosynthesis
-
RNA-Binding Protein EWS / genetics
-
RNA-Binding Protein EWS / physiology*
-
Recombinant Fusion Proteins / biosynthesis
-
Recombinant Fusion Proteins / genetics
-
Recombinant Fusion Proteins / physiology*
-
Transcription Factors / biosynthesis
-
Transcription Factors / genetics
-
Transcription Factors / physiology*
-
Transcription, Genetic
-
Transfection
-
Up-Regulation
-
Uridine Phosphorylase / biosynthesis
-
Uridine Phosphorylase / genetics
-
Uridine Phosphorylase / physiology*
-
ras Proteins / physiology
Substances
-
EWS-FLI fusion protein
-
Oncogene Proteins, Fusion
-
Proto-Oncogene Protein c-fli-1
-
Proto-Oncogene Proteins
-
Proto-Oncogene Proteins c-ets
-
RNA-Binding Protein EWS
-
Recombinant Fusion Proteins
-
Transcription Factors
-
Floxuridine
-
DNA
-
Uridine Phosphorylase
-
ras Proteins
-
doxifluridine