Negative regulation-resistant p53 variant enhances oncolytic adenoviral gene therapy

Hum Gene Ther. 2012 Jun;23(6):609-22. doi: 10.1089/hum.2011.114. Epub 2012 Feb 21.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics*
  • Animals
  • Blotting, Western
  • Cell Line
  • Cell Line, Tumor
  • Down-Regulation
  • Genetic Therapy*
  • Genetic Variation
  • Genetic Vectors*
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Microscopy, Electron, Transmission
  • Neoplasms / pathology
  • Neoplasms / therapy*
  • Transcriptional Activation
  • Tumor Suppressor Protein p53 / genetics*


  • Tumor Suppressor Protein p53