Isolation and molecular characterization of the 5 '-upstream region of thehuman TRAIL gene

TRAIL, a novel member of the TNF family, acts through membrane receptors to induce apoptosis of activated T lymphocytes and may represent a mechanism for the "immune escape" of certain cancers. Various cytokines appear to inc rease expression of other TNF family members; however, the regulation of TR AIL has not been defined. The purpose of this study was to assess molecular mechanisms regulating TRAIL gene expression in human colon cancers. In thi s study, we have cloned the human TRAIL (hTRAIL) promoter (similar to 1.6 k b) and identified a number of putative transcription factor binding sites s uch as NFAT, AP-1 and Spl sequences which are important for the expression of other TNF family members. Transient transfections of 5'-deletion promote r constructs into either Caco-2 or HT29 colon cancer cells identified TRAIL promoter regions critical for both basal and interferon-gamma (IFN-gamma)- mediated induction. Furthermore, induction of TRAIL mRNA levels was demonst rated in HT29 and Caco-2 cells with IFN-gamma treatment suggesting an impor tant role for this cytokine in TRAIL expression. (C) 2000 Academic Press.