title: Negative regulation-resistant p53 variant enhances oncolytic adenoviral gene therapy.
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 (p53VPΔ30) 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-mΔ19 expressing p53VPΔ30 (Ad-mΔ19/p53VPΔ30) showed greater cytotoxicity than Ad-mΔ19 expressing wild-type p53 or other p53 variants in human cancer cell lines. We found that Ad-mΔ19/p53VPΔ30 induced apoptosis through accumulation of p53VPΔ30, regardless of endogenous p53 and Mdm2 status. Moreover, Ad-mΔ19/p53VPΔ30 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-mΔ19/p53VPΔ30 shows potential for improving p53-mediated cancer gene therapy.
authors.affiliation: Brain Korea 21 Project for Medical Science, Institute for Cancer Research, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 120-752, Korea.
authors.forename: Taeyoung
authors.initials: T
authors.lastname: Koo
authors.forename: Il-Kyu
authors.initials: IK
authors.lastname: Choi
authors.forename: Minjung
authors.initials: M
authors.lastname: Kim
authors.forename: Jung-Sun
authors.initials: JS
authors.lastname: Lee
authors.forename: Eonju
authors.initials: E
authors.lastname: Oh
authors.forename: Jungho
authors.initials: J
authors.lastname: Kim
authors.forename: Chae-Ok
authors.initials: CO
authors.lastname: Yun
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D015536:Down-Regulation; D015316:Genetic Therapy; D014644:Genetic Variation; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D046529:Microscopy, Electron, Transmission; D009369:Neoplasms / Q000473:pathology / Q000628:therapy*; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D016159:Tumor Suppressor Protein p53