Regulated expression of the diphtheria toxin A chain by a tumor-specific chimeric transcription factor results in selective toxicity for alveolar rhabdomyosarcoma cells
| العنوان: | Regulated expression of the diphtheria toxin A chain by a tumor-specific chimeric transcription factor results in selective toxicity for alveolar rhabdomyosarcoma cells |
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| المؤلفون: | Edward J. Dunphy, Rebecca A. Redman, Timothy P. Cripe, Frederic G. Barr, Edmond S. Massuda, Jennifer J. Schreiber, Ian H. Maxwell, Lauren E. Nauta |
| المصدر: | Proceedings of the National Academy of Sciences. 94:14701-14706 |
| بيانات النشر: | Proceedings of the National Academy of Sciences, 1997. |
| سنة النشر: | 1997 |
| مصطلحات موضوعية: | Recombinant Fusion Proteins, Muscle Proteins, Nerve Tissue Proteins, Biology, Plasmid, Gene expression, Humans, Cytotoxic T cell, Diphtheria Toxin, Rhabdomyosarcoma, Alveolar, Homeodomain Proteins, Diphtheria toxin, Regulation of gene expression, Reporter gene, Multidisciplinary, Forkhead Box Protein O1, Gene Transfer Techniques, PAX7 Transcription Factor, Forkhead Transcription Factors, Genetic Therapy, Transfection, Biological Sciences, Fusion protein, Molecular biology, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, HeLa Cells, Transcription Factors |
| الوصف: | Alveolar rhabdomyosarcoma (ARMS) cells often harbor one of two unique chromosomal translocations, either t(2;13)(q35;q14) or t(1;13)(p36;q14). The chimeric proteins expressed from these rearrangements, PAX3-FKHR and PAX7-FKHR, respectively, are potent transcriptional activators. In an effort to exploit these unique cancer-specific molecules to achieve ARMS-specific expression of therapeutic genes, we have studied the expression of a minimal promoter linked to six copies of a PAX3 DNA binding site, prs-9. In transient transfections, expression of the prs-9-regulated reporter genes was ≈250-fold higher than expression of genes lacking the prs-9 sequences in cell lines derived from ARMS, but remained at or below baseline levels in other cells. High expression of these prs-9-regulated genes was also observed in a cancer cell line that lacks t(2;13) but was stably transfected with a plasmid expressing PAX3-FKHR. Transfection of a plasmid containing the diphtheria toxin A chain gene regulated by prs-9 sequences (pA3–6PED) was selectively cytotoxic for PAX3-FKHR-expressing cells. This was shown by inhibition of gene expression from cotransfected plasmids and by direct cytotoxicity after transfected cells were isolated by cell sorting. Gene transfer of pA3–6PED may thus be useful as a cancer-specific treatment strategy for t(2;13)- or t(1;13)-positive ARMS. Furthermore, gene transfer of fusion protein-regulated toxin genes might also be applied to the treatment of other cancers that harbor cancer-specific chromosomal translocations involving transcription factors. |
| تدمد: | 1091-6490 0027-8424 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4519ca9707d12d2b62a944d6c3c48b3f https://doi.org/10.1073/pnas.94.26.14701 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....4519ca9707d12d2b62a944d6c3c48b3f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10916490 00278424 |
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