TAR1, A Human Anti-p53 Single-Chain Antibody, Restores Tumor Suppressor Function to Mutant p53 Variants
| Autor: | Itai Benhar, Hemi Dimant, Beka Solomon, Ronit Azriel-Rosenfeld, Eyal Dor-On, Sara Orgad |
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| Rok vydání: | 2010 |
| Předmět: |
Transcriptional Activation
Cancer Research Tumor suppressor gene Immunology Mutant Mice Nude Apoptosis Plasma protein binding Biology medicine.disease_cause Mice Cell Line Tumor medicine Animals Humans Immunology and Allergy Gene Cell Proliferation Caspase 7 Pharmacology Mutation Caspase 3 Point mutation Neoplasms Experimental Xenograft Model Antitumor Assays Molecular biology Tumor Burden Cell culture Cancer cell Mutant Proteins Tumor Suppressor Protein p53 Protein Binding Signal Transduction Single-Chain Antibodies |
| Zdroj: | Journal of Immunotherapy. 33:146-154 |
| ISSN: | 1524-9557 |
| DOI: | 10.1097/cji.0b013e3181be14dc |
| Popis: | The tumor suppressor gene p53 is mutated in more than half of human tumors. One important characteristic of p53 mutants is their accumulation in the nucleus of cancer cells. Thus, reactivation of mutant p53 proteins may trigger massive apoptosis in tumor cells. Pharmacologic methods are currently under development to induce mutant p53 proteins to resume their wild-type function. We have identified a human single-chain Fv fragment, designated as transcriptional transactivation and apoptosis restoring (TAR1), which specifically and with high affinity binds to mutant p53 and restores its wild-type active conformation. Binding of TAR1 to mutant p53 induced transcriptional transactivation of p53 target genes and down-regulation of mutant p53 transcriptional target genes. TAR1 treatment induced apoptosis in a variety of cell lines endogenously expressing p53 carrying different point mutations DNA contact or structural p53 mutants. Moreover, in an animal model of mice carrying human xenografts, TAR1 induced tumor regression with no apparent deleterious side effects. Thus, it may be considered as a potential candidate for anticancer treatment, targeting tumors with mutant p53. |
| Databáze: | OpenAIRE |
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