Negative Regulation-Resistant p53 Variant Enhances Oncolytic Adenoviral Gene Therapyopen access
- Authors
- Koo, Taeyoung; Choi, Il-Kyu; Kim, Minjung; Lee, Jung-Sun; Oh, Eonju; Kim, Jungho; Yun, Chae-Ok
- Issue Date
- Jun-2012
- Publisher
- MARY ANN LIEBERT INC
- Citation
- HUMAN GENE THERAPY, v.23, no.6, pp.609 - 622
- Indexed
- SCIE
SCOPUS
- Journal Title
- HUMAN GENE THERAPY
- Volume
- 23
- Number
- 6
- Start Page
- 609
- End Page
- 622
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/27527
- DOI
- 10.1089/hum.2011.114
- ISSN
- 1043-0342
- Abstract
- Intact p53 function is essential for responsiveness to cancer therapy. However, p53 activity is attenuated by the proto-oncoprotein Mdm2, the adenovirus protein E1B 55kD, and the p53 C-terminal domain. To confer resistance to Mdm2, E1B 55kD, and C-terminal negative regulation, we generated a p53 variant (p53VP Delta 30) by deleting the N-terminal and C-terminal regions of wild-type p53 and inserting the transcriptional activation domain of herpes simplex virus VP16 protein. The oncolytic adenovirus vector Ad-m Delta 19 expressing p53VP Delta 30 (Ad-m Delta 19/p53VP Delta 30) showed greater cytotoxicity than Ad-m Delta 19 expressing wild-type p53 or other p53 variants in human cancer cell lines. We found that Ad-m Delta 19/p53VP Delta 30 induced apoptosis through accumulation of p53VP Delta 30, regardless of endogenous p53 and Mdm2 status. Moreover, Ad-m Delta 19/p53VP Delta 30 showed a greater antitumor effect and increased survival rates of mice with U343 brain cancer xenografts that expressed wild-type p53 and high Mdm2 levels. To our knowledge, this is the first study reporting a p53 variant modified at the N terminus and C terminus that shows resistance to degradation by Mdm2 and E1B 55kD, as well as negative regulation by the p53 C terminus, without decreased trans-activation activity. Taken together, these results indicate that Ad-m Delta 19/p53VP Delta 30 shows potential for improving p53-mediated cancer gene therapy.
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