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pubmed-article:14681724pubmed:abstractTextAdenoviral gene expression that is repressed by p53 in nontransformed cells could provide a tumor-specific gene therapy approach for a large subset of tumors. Adenoviral infection in vivo induces stabilization of p53, which can be utilized for a strategy that includes p53-dependent expression of a transcriptional repressor and a target promoter,which is highly susceptible for transcriptional repression. Therefore, we constructed different versions of CMV-promoters (CMVgal) with binding sites for GAL4-DBD and investigated 11 GAL4-DBD fusion proteins to elucidate the most effective repressor domain to silence CMVgal activity. The transcriptional repressor GAL4-KRAB-A under control of a p53-dependent promoter facilitates strong CMVgal-mediated gene expression specifically in p53 mutant cells by a double-recombinant adenoviral vector (Ad-RGCdR). GAL4-KRAB-A mediates strong transcriptional repression of Ad-RGCdR in p53 wild-type cells, which could be further enhanced by preactivation of p53-signalling following low-dose chemotherapy prior to adenoviral infection. By utilizing p53 signalling involved in chemotherapy and adenoviral infection, more than 99% of Ad-RGCdR gene expression could be repressed in p53 wild-type cells. Controlled gene expression from CMVgal promoters by transcriptional repression utilizing functional p53 signalling thus provides a very effective tool for tumor-specific adenoviral gene therapy.lld:pubmed
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pubmed-article:14681724pubmed:dateRevised2009-11-3lld:pubmed
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pubmed-article:14681724pubmed:articleTitleTumor-specific adenoviral gene therapy: transcriptional repression of gene expression by utilizing p53-signal transduction pathways.lld:pubmed
pubmed-article:14681724pubmed:affiliationDepartment of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Carl Neuberg Str. 1, 30625 Hannover, Germany.lld:pubmed
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pubmed-article:14681724pubmed:publicationTypeResearch Support, Non-U.S. Gov'tlld:pubmed
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