Development of an adenoviral vector with robust expression driven by p53.
Here we introduce a new adenoviral vector where transgene expression is driven by p53. We first developed a synthetic promoter, referred to as PGTxbeta, containing a p53-responsive element, a minimal promoter and the first intron of the rabbit beta-globin gene. Initial assays using plasmid-based vectors indicated that expression was tightly controlled by p53 and was 5-fold stronger than the constitutive CMV immediate early promoter/enhancer. The adenoviral vector, AdPG, was also shown to offer p53-responsive expression in prostate carcinoma cells LNCaP (wt p53), DU-145 (temperature sensitive mutant of p53) and PC3 (p53-null, but engineered to express temperature-sensitive p53 mutants). AdPG served as a sensor of p53 activity in LNCaP cells treated with chemotherapeutic agents. Since p53 can be induced by radiotherapy and chemotherapy, this new vector could be further developed for use in combination with conventional therapies to bring about cooperation between the genetic and pharmacologic treatment modalities.
Bajgelman
Marcio C
MC
Viral Vector Group, Laboratory of Genetics and Molecular Cardiology/LIM 13, Heart Institute (InCor), University of Sao Paulo School of Medicine, Brazil.
Strauss
Bryan E
BE
D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D045744:Cell Line, Tumor; D018076:DNA, Complementary; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000627:therapeutic use; D004742:Enhancer Elements, Genetic; D017930:Genes, Reporter; D016158:Genes, p53; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007438:Introns; D008156:Luciferases / Q000378:metabolism; D008297:Male; D017239:Paclitaxel / Q000627:therapeutic use; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology / Q000532:radiotherapy; D011817:Rabbits; D014161:Transduction, Genetic; D014162:Transfection; D019076:Transgenes
D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D018076:DNA, Complementary; D004317:Doxorubicin; D008156:Luciferases; D017239:Paclitaxel