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Interferon -dependent Induction of Thymidine Phosphorylase/Platelet-derived Endothelial Growth Factor through -Activated Sequence-like Element in Human Macrophages¹

Department of Medical Biochemistry, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582 [H. G., M. K., M. O.]; Department of Molecular Biology, University of Occupational and Environmental Health, Kita-Kyushu 807-8555[K. K.]; Third Department of Internal Medicine, University of Tokushima School of Medicine, Tokushima 770-8503 [H. G., S. S.]; and Department of Cancer Chemotherapy, Institute for Cancer Research, Faculty of Medicine, Kagoshima University, Kagoshima 890-8520 [S-i. A.], Japan

Thymidine phosphorylase (TP), an enzyme involved in the reversible conversion of thymidine to thymine, is identical to platelet-derived endothelial cell growth factor. TP expression in cancer cells and/or infiltrated macrophages is associated with microvessel density and poor clinical prognosis in patients with various tumor types. However, how TP expression is up-regulated in human tumors is unclear. Of various inflammatory cytokines, such as tumor necrosis factor (TNF-), interleukin 1 (IL-1), and interferon (IFN-), we observed that IFN- most effectively increased the expression of TP in cultured human monocytic U937 cells. Transient transfection of the various deletion constructs of the TP promoter showed that the presence of the -474 to -355 sequence containing -activated sequence-like element was essential for IFN--dependent activation of the TP gene. Furthermore, the IFN--dependent transcriptional activity of the promoter construct containing mutations in the -activated sequence-like element was significantly decreased. An electrophoretic mobility shift assay showed that IFN- increased signal transducers and activators of transcription 1 binding to -activated sequence-like element in the TP promoter. IFN- could be a mediator of TP expression in infiltrated monocyte/macrophages, and those monocyte/macrophages expressing TP might play an important role in malignancy and angiogenesis in various human tumors.

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