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Gene Ther. 2014 Oct;21(10):903-12. doi: 10.1038/gt.2014.70. Epub 2014 Jul 31.

Re-engineered p53 activates apoptosis in vivo and causes primary tumor regression in a dominant negative breast cancer xenograft model.

Author information

1
Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, USA.
2
1] Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, USA [2] Department of Pharmaceutics and Biopharmacy, Philipps-Universität, Marburg, Germany.
3
Faculty of Biotechnology, Biberach University of Applied Sciences, Biberach, Germany.
4
Department of Pathology, University of Utah, Salt Lake City, UT, USA.
5
1] Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, USA [2] Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, UT, USA [3] Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
6
1] Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, USA [2] Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.

Abstract

Inactivation of p53 pathway is reported in more than half of all human tumors and can be correlated to malignant development. Missense mutation in the DNA binding region of p53 is the most common mechanism of p53 inactivation in cancer cells. The resulting tumor-derived p53 variants, similar to wild-type (wt) p53, retain their ability to oligomerize via the tetramerization domain. Upon hetero-oligomerization, mutant p53 enforces a dominant negative effect over active wt-p53 in cancer cells. To overcome this barrier, we have previously designed a chimeric superactive p53 (p53-CC) with an alternative oligomerization domain capable of escaping transdominant inhibition by mutant p53 in vitro. In this report, we demonstrate the superior tumor suppressor activity of p53-CC and its ability to cause tumor regression of the MDA-MB-468 aggressive p53-dominant negative breast cancer tumor model in vivo. In addition, we illustrate the profound effects of the dominant negative effect of endogenous mutant p53 over wt-p53 in cancer cells. Finally, we investigate the underlying differential mechanisms of activity for p53-CC and wt-p53 delivered using viral-mediated gene therapy approach in the MDA-MB-468 tumor model.

PMID:
25077773
PMCID:
PMC4324557
DOI:
10.1038/gt.2014.70
[Indexed for MEDLINE]
Free PMC Article

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