Regulation of expression of thymidine phosphorylase/platelet-derived endothelial cell growth factor in human colon carcinoma cells

E L Schwartz, E Wan, F S Wang, N Baptiste
1998 Cancer Research  
The enzyme/cytokine thymidine phosphorylase/platelet-derived endothelial cell growth factor (TP/PD-ECGF) has diverse functions within cells, including the regulation of steady-state thymidine levels, the conversion of cancer chemotherapeutic agent 5-fluorouracil to an active metabolite, and the mediation of angiogenesis in normal and malignant cells. Although the level of TP/PD-ECGF expression varies substantially among different individuals, is usually elevated in colorectal tumors compared to
more » ... tumors compared to nonmalignant tissue, and has been shown to be directly associated with poor clinical prognosis, little is known about the mechanisms for control of TP/PD-ECGF expression. TP/PD-ECGF mRNA levels are extremely low in most cell lines in vitro, including HT29 human colon carcinoma cells. IFN-alpha and IFN-beta induced an increase in TP/PD-ECGF enzyme activity and mRNA levels. The induction of TP/PD-ECGF expression by IFN was not as strong as that of another IFN-inducible gene, 2'-5' oligoadenylate synthetase, but in contrast to 2'-5' oligoadenylate synthetase, TP/PD-ECGF mRNA levels remained elevated for up to 72 h. Experiments suggested that this was due to the combination of a rapid but transient increase in the rate of TP/PD-ECGF transcription that was accompanied by a more prolonged stabilization of TP/PD-ECGF mRNA. Using an electrophoretic mobility shift assay, IFN was found to rapidly and transiently induce nuclear factors that bound to a putative IFN response element in the TP/PD-ECGF promoter. The complex observed was similar but not identical to that seen using the consensus IFN-stimulated response element sequence as a target. TP/PD-ECGF mRNA also has a pyrimidine-rich sequence at its 3' end that was similar to a motif that has been reported to mediate increased mRNA stability in other genes. These studies indicate that TP/PD-ECGF gene expression was subject to regulation by both transcriptional and posttranscriptional mechanisms.
pmid:9537263 fatcat:gtbuys6545eolholr6nf45b4iq