A novel approach to cancer treatment using structural hybrids of the p53 gene family.

Abstract

The p53 tumor suppressor belongs to a gene family that includes two other structurally and functionally related members: p73 and p63. The regulation of p53 activity differs significantly from that of p73 and p63. To enhance the tumor suppressive activity of p53, we constructed six recombinant adenoviruses that encode hybrid proteins with three functional domains derived from either p53 or TAp63γ. The potency of these hybrid molecules in suppressing tumorigenesis was evaluated using in vitro and in vivo models. Of the hybrid molecules tested, one hybrid named p63-53O was the most potent activator of apoptosis in human cancer cells. The p63-53O hybrid is composed of the transcriptional activation domain and DNA-binding domain of TAp63γ and the oligomerization domain of p53. The p63-53O hybrid efficiently transactivated p53AIP1. Moreover, silencing of p53AIP1 partially abolished the apoptotic response to p63-53O in human cancer cells. The p53-p63 hybrid molecule is a novel potent anti-proliferative agent for the treatment of cancer.

• Authors: Y Sasaki, Y Oshima, R Koyama, M Tamura, L Kashima, M Idogawa, T Yamashita, M Toyota, K Imai, Y Shinomura, T Tokino
• Journal: Cancer gene therapy (Cancer Gene Ther) Vol. 19 Issue 11 Pg. 749-56 (Nov 2012) ISSN: 1476-5500 [Electronic] England
• PMID: 22956039 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• P53AIP1 protein, human
• Recombinant Fusion Proteins
• TP53 protein, human
• TP63 protein, human
• Transcription Factors
• Tumor Suppressor Protein p53
• Tumor Suppressor Proteins

Topics

• Adenoviridae (genetics, metabolism)
• Animals
• Antineoplastic Agents (administration & dosage, pharmacology)
• Apoptosis
• Apoptosis Regulatory Proteins (genetics, metabolism)
• Cell Line, Tumor
• Cell Transformation, Neoplastic (metabolism, pathology)
• Female
• Gene Expression Regulation, Neoplastic
• Genes, p53
• Genetic Vectors (genetics, metabolism)
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasms (genetics, metabolism, therapy)
• Protein Structure, Tertiary
• Recombinant Fusion Proteins (administration & dosage, metabolism, therapeutic use)
• Transcription Factors (genetics, metabolism)
• Transcriptional Activation
• Tumor Suppressor Protein p53 (genetics, metabolism)
• Tumor Suppressor Proteins (genetics, metabolism)
• Xenograft Model Antitumor Assays