ISOLATION OF AN X-RAY-RESPONSIVE ELEMENT IN THE PROMOTER REGION OF TISSUE-TYPE PLASMINOGEN-ACTIVATOR - POTENTIAL USES OF X-RAY-RESPONSIVE ELEMENTS FOR GENE-THERAPY

Tissue-type plasminogen activator (t-PA) was induced over 50-fold afte r X irradiation in radioresistant human melanoma cells (Boothman ef al ., Cancer Res. 51, 5587-5595, 1991). Activities of t-PA were induced 1 4-fold in ataxia telangiectasia, 9-fold in Bloom's syndrome and 6-fold in Fanconi's anemia cells, compared to normal human fibroblasts (Fuku naga et al., Int. J. Radiat. Oncol. Biol. Phys. 24, 949-957, 1992). X- ray-inducible synthesis of the protease, t-PA, may play a role(s) in d amage-inducible repair processes in mammalian cells, similar to the SO S repair systems in lower eukaryotes and prokaryotes. DNA band shift a nd DNase I footprinting assays were used to determine binding if trans cription factors to a previously unknown X-ray-responsive element (XRE ) in the t-PA promoter. The major goals of our research with XREs are to understand (a) which transcription factor(s) regulates t-PA inducti on after X rays, and (b) the role(s) of t-PA in DNA repair, apoptosis or other responses to X rays. The purpose of this paper is to discuss the potential use of an XRE, such as the one in the t-PA. promoter, fo r gene radiotherapy. Several gene therapy strategies are proposed.