Activation of Stat1, IRF-1, and NF-B is Required for the Induction of Uridine Phosphorylase by Tumor Necrosis Factor- and Interferon-

作者：Wan Laxiang; Cao Deliang; Zeng Jianmin; Ziemba Amy; Pizzorno Giuseppe^*

来源：Nucleosides Nucleotides & Nucleic Acids, 2010, 29(4-6): 488-503.

DOI：10.1080/15257771003729682

• TNF-
• IFN-
• gene expression regulation
• NF-B
• STAT-1
• IRF-1
• promoter analysis

Uridine phosphorylase (UPase) has been shown to be induced in various human and murine tumors and could potentially serve as a specific target for the modulation of tumor-selectivity of fluoropyrimidines. However, the signaling mechanisms underlying the regulation of UPase gene expression have not been determined. In this study, we investigated the effects of IFN- on the regulation of TNF--induced UPase activity and have uncovered the molecular mechanisms of this potentiation, utilizing murine EMT6 breast cancer cells. Our data has shown that IFN- can significantly increase UPase mRNA expression and the enzymatic activity induced by TNF- in a dose-dependent manner, resulting in an enhanced sensitivity to 5-fluorouracil (5-FU) and 5'-Deoxy-5-fluorouridine (5'DFUR). We have previously shown that TNF- activates NF-B through increased translocation of NF-B p65 from the cytoplasm into the nuclei. Exposure to IFN- mainly affects nuclear IRF-1 and STAT1 in EMT6, but inhibits NF-B p65 activity, indicating that the cooperative stimulation was the result of the independent activation of NF-B, STAT1 and IRF-1 transcriptional factors through binding to their unique sites in the UPase promoter. Notably, the activation of NF-B and STAT1 in human breast tissues is consistent with UPase activity; signifying their role in the up-regulation of the UPase gene expression in human tumors.

• 出版日期2010