Omomyc Reveals New Mechanisms To Inhibit the MYC Oncogene
| Autor: | Abbas Walji, John Zelina, Federica Orvieto, Smaranda Bodea, Simona Altezza, Derek Wiswell, Mark J Demma, Shiying Chen, Jennifer O'Neil, Enrique Escandón, Eric S. Muise, Alessia Santoprete, Brian Hall, Claudio Mapelli, Benjamin Ruprecht, Angie Sun, Kallol Ray, Federica Tucci, Sarah Javaid |
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| Rok vydání: | 2019 |
| Předmět: |
Transcriptional Activation
Chromatin Immunoprecipitation Transcription Genetic Genes myc E-box Myc cotranslational Biology Ribosome Cell Line Proto-Oncogene Proteins c-myc Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Transcription (biology) Cell Line Tumor Animals Humans Amino Acid Sequence DNA binding rRNA Promoter Regions Genetic Molecular Biology 030304 developmental biology Mice Inbred BALB C 0303 health sciences Oncogene Basic Helix-Loop-Helix Leucine Zipper Transcription Factors RNA Promoter DNA Cell Biology HCT116 Cells Peptide Fragments Recombinant Proteins Cell biology DNA-Binding Proteins chemistry Omomyc 030220 oncology & carcinogenesis Female transcription Chromatin immunoprecipitation Protein Binding Research Article Max |
| Zdroj: | Molecular and Cellular Biology |
| ISSN: | 1098-5549 |
| DOI: | 10.1128/mcb.00248-19 |
| Popis: | The MYC oncogene is upregulated in human cancers by translocation, amplification, and mutation of cellular pathways that regulate Myc. Myc/Max heterodimers bind to E box sequences in the promoter regions of genes and activate transcription. The MYC oncogene is upregulated in human cancers by translocation, amplification, and mutation of cellular pathways that regulate Myc. Myc/Max heterodimers bind to E box sequences in the promoter regions of genes and activate transcription. The MYC inhibitor Omomyc can reduce the ability of MYC to bind specific box sequences in promoters of MYC target genes by binding directly to E box sequences as demonstrated by chromatin immunoprecipitation (CHIP). Here, we demonstrate by both a proximity ligation assay (PLA) and double chromatin immunoprecipitation (ReCHIP) that Omomyc preferentially binds to Max, not Myc, to mediate inhibition of MYC-mediated transcription by replacing MYC/MAX heterodimers with Omomyc/MAX heterodimers. The formation of Myc/Max and Omomyc/Max heterodimers occurs cotranslationally; Myc, Max, and Omomyc can interact with ribosomes and Max RNA under conditions in which ribosomes are intact. Taken together, our data suggest that the mechanism of action of Omomyc is to bind DNA as either a homodimer or a heterodimer with Max that is formed cotranslationally, revealing a novel mechanism to inhibit the MYC oncogene. We find that in vivo, Omomyc distributes quickly to kidneys and liver and has a short effective half-life in plasma, which could limit its use in vivo. |
| Databáze: | OpenAIRE |
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