Reactivation of mutant p53 and induction of apoptosis in human tumor cells by maleimide analogs
| Autor: | Vladimir J.N. Bykov, Alexandre Shilov, Monica Hultcrantz, Klas G. Wiman, Galina Selivanova, Nicole Zache, Jan Bergman, Natalia Issaeva |
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| Rok vydání: | 2017 |
| Předmět: |
Transcriptional Activation
Programmed cell death Protein Conformation Mutant Antineoplastic Agents Enzyme-Linked Immunosorbent Assay Cell Separation Mice SCID Plasma protein binding Biology medicine.disease_cause Biochemistry Maleimides Mice In vivo Cell Line Tumor Neoplasms medicine Animals Humans Molecular Biology Glutathione Transferase Mutation Dose-Response Relationship Drug DNA Cell Biology Tetracycline Flow Cytometry In vitro Cell biology Microscopy Fluorescence Models Chemical Apoptosis Cell culture Immunology Additions and Corrections Tumor Suppressor Protein p53 Neoplasm Transplantation Plasmids Protein Binding |
| Zdroj: | The Journal of biological chemistry. 292(48) |
| ISSN: | 1083-351X |
| Popis: | Reactivation of mutant p53 is likely to provide important benefits for treatment of chemotherapy- and radiotherapy-resistant tumors. We demonstrate here that the maleimide-derived molecule MIRA-1 can reactivate DNA binding and preserve the active conformation of mutant p53 protein in vitro and restore transcriptional transactivation to mutant p53 in living cells. MIRA-1 induced mutant p53-dependent cell death in different human tumor cells carrying tetracycline-regulated mutant p53. The structural analog MIRA-3 showed antitumor activity in vivo against human mutant p53-carrying tumor xenografts in SCID mice. The MIRA scaffold is a novel lead for the development of anticancer drugs specifically targeting mutant p53. |
| Databáze: | OpenAIRE |
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