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Targeting gene expression selectively in cancer cells by using the progression-elevated gene-3 promoter Su ZZ; Sarkar D; Emdad L; Duigou GJ; Young CS; Ware J; Randolph A; Valerie K; Fisher PBProc Natl Acad Sci U S A 2005[Jan]; 102 (4): 1059-64One impediment to effective cancer-specific gene therapy is the rarity of regulatory sequences targeting gene expression selectively in tumor cells. Although many tissue-specific promoters are recognized, few cancer-selective gene promoters are available. Progression-elevated gene-3 (PEG-3) is a rodent gene identified by subtraction hybridization that displays elevated expression as a function of transformation by diversely acting oncogenes, DNA damage, and cancer cell progression. The promoter of PEG-3, PEG-Prom, displays robust expression in a broad spectrum of human cancer cell lines with marginal expression in normal cellular counterparts. Whereas GFP expression, when under the control of a CMV promoter, is detected in both normal and cancer cells, when GFP is expressed under the control of the PEG-Prom, cancer-selective expression is evident. Mutational analysis identifies the AP-1 and PEA-3 transcription factors as primary mediators of selective, cancer-specific expression of the PEG-Prom. Synthesis of apoptosis-inducing genes, under the control of the CMV promoter, inhibits the growth of both normal and cancer cells, whereas PEG-Prom-mediated expression of these genes kills only cancer cells and spares normal cells. The efficacy of the PEG-Prom as part of a cancer gene therapeutic regimen is further documented by in vivo experiments in which PEG-Prom-controlled expression of an apoptosis-inducing gene completely inhibited prostate cancer xenograft growth in nude mice. These compelling observations indicate that the PEG-Prom, with its cancer-specific expression, provides a means of selectively delivering genes to cancer cells, thereby providing a crucial component in developing effective cancer gene therapies.|*Genetic Therapy[MESH]|Animals[MESH]|Antigens, Differentiation/*genetics[MESH]|Cell Cycle Proteins[MESH]|Genes, Tumor Suppressor[MESH]|Humans[MESH]|Interleukins/genetics[MESH]|Male[MESH]|Mice[MESH]|Neoplasm Proteins/*genetics[MESH]|Neoplasms/*therapy[MESH]|Promoter Regions, Genetic[MESH]|Protein Phosphatase 1[MESH]|Proteins/genetics[MESH]|Proto-Oncogene Proteins[MESH]|Transcription Factor AP-1/physiology[MESH]|Transcription Factors/physiology[MESH] |
