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Doctoral Thesis
DOI
10.11606/T.87.2011.tde-14092011-144755
Document
Author
Full name
Rafael Bento da Silva Soares
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2011
Supervisor
Committee
Strauss, Bryan Eric (President)
Jasiulionis, Miriam Galvonas
Maria, Durvanei Augusto
Vasques, Luciana dos Reis
Ventura, Armando Morais
Title in Portuguese
Construção e caracterização de vetor adenoviral com promotor responsivo ao seu próprio transgene p53 e sua comparação com um vetor de promoção constitutiva.
Keywords in Portuguese
Adenovírus genética
Apoptose
Expressão gênica
Neoplasia genética
Terapia biológica
Transferência de genes
Abstract in Portuguese
Em sua maioria, estratégias de transferência gênica utilizam arranjos com promotores e transgenes funcionando de maneira independente entre si, como é o caso do amplamente utilizado promotor CMV. Nosso grupo foge dessa linha de promotores/transgenes independentes. Desenvolvemos uma nova estratégia de transferência gênica que combina estrategicamente a atividade do transgene e o do promotor de expressão gênica, onde o promotor foi modificado com a inserção do elemento PG, responsívo a p53. Neste trabalho construímos um novo vetor adenoviral (AdPGp53) contendo o gene da proteína supressora de tumor p53 cuja expressão é controlada por ela própria através do elemento PG. Em comparação com um vetor adenoviral que possui o gene da p53 sob ação do promotor tradicional CMV (AdCMVp53), o vetor AdPGp53 apresentou expressão superior de p53 em células humanas de carcinoma de próstata PC3, maior morte celular in vitro e parece ter diminuído o ritmo de crescimento tumoral in vivo em um modelo xenográfico de células PC3 em camundongos atímicos.
Title in English
Construction and characterization of an adenoviral vector responsive to its own p53 transgene in a comparison with a constitutive promoter vector.
Keywords in English
Apoptosis
Biological therapy
Cancer genetics
Gene expression
Gene transfer
Genetic adenovirus
Abstract in English
The majority of gene therapy strategies in use today are based on promoters and transgenes that work independently, and an example of this is the widely used CMV promoter. Our group breaks way from the use of independent promoter/transgene activity. We developed a new gene transfer strategy which combines the transgene activity and the promoter of gene expression. This was achieved by the insertion of the PG element, which is a p53-responsive enhancer, in the promoter. In the present work we built a new adenoviral vector (AdPGp53) containing the p53 tumor suppressor gene, whose expression is controlled by the p53 protein itself through the PG element. In comparative experiments, in which we used our AdPGp53 vector and another adenoviral vector, with a p53 gene and a traditional CMV promoter (AdCMVp53), our vector showed superior p53 expression in PC3 human prostate cancer cells, superior cell death in vitro and a tendency in diminishing tumor growth in an in vivo xenograft model in nude mice injected with PC3 cells.
 
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Publishing Date
2011-09-22
 
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