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 after X irradiation in radioresistant human melanoma cells (Boothman et al., Cancer Res. 51, 5587-5595, 1991). Activities of t-PA were induced 14-fold in ataxia telangiectasia, 9-fold in Bloom's syndrome and 6-fold in Fanconi's anemia cells, compared to normal human fibroblasts (Fukunaga 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 damage-inducible repair processes in mammalian cells, similar to the SOS repair systems in lower eukaryotes and prokaryotes. DNA band shift and DNase I footprinting assays were used to determine binding if transcription 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 induction 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, for gene radiotherapy. Several gene therapy strategies are proposed.
Boothman
D A
DA
Department of Human Oncology (K4/626), University of Wisconsin-Madison 53792.
Lee
I W
IW
Sahijdak
W M
WM
D002467:Cell Nucleus / Q000201:enzymology; D004307:Dose-Response Relationship, Radiation; D015316:Genetic Therapy; D006801:Humans; D011401:Promoter Regions, Genetic / Q000528:radiation effects*; D010959:Tissue Plasminogen Activator / Q000096:biosynthesis / Q000235:genetics* / Q000528:radiation effects; D014407:Tumor Cells, Cultured
D010959:Tissue Plasminogen Activator