Nuclear localized Raf1 isoform alters DNA‐dependent protein kinase activity and the DNA damage response
| Autor: | Michael S Glennon, Michael L. Freeman, Emily S. Kounlavong, Jason R Becker, Eric J. Hall, Sara C. Sebag, Benjamin R. Nixon |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Gene isoform MAPK/ERK pathway DNA damage Apoptosis DNA-Activated Protein Kinase Biochemistry Tacrolimus Binding Proteins Bleomycin 03 medical and health sciences 0302 clinical medicine Cell Line Tumor Genetics Humans Protein Isoforms Extracellular Signal-Regulated MAP Kinases Protein kinase A Molecular Biology Cell Nucleus Antibiotics Antineoplastic biology Chemistry Research DNA Cell biology Proto-Oncogene Proteins c-raf Alternative Splicing HEK293 Cells 030104 developmental biology Protein kinase domain Chaperone (protein) ras Proteins biology.protein Signal transduction 030217 neurology & neurosurgery Nuclear localization sequence DNA Damage Protein Binding Signal Transduction Biotechnology |
| Zdroj: | The FASEB Journal. 33:1138-1150 |
| ISSN: | 1530-6860 0892-6638 |
| Popis: | Raf1/c-Raf is a well-characterized serine/threonine-protein kinase that links Ras family members with the MAPK/ERK signaling cascade. We have identified a novel splice isoform of human Raf1 that causes protein truncation and loss of the C-terminal kinase domain (Raf1-tr). We found that Raf1-tr has increased nuclear localization compared with full-length Raf1, and this finding was secondary to reduced binding of Raf1-tr to the cytoplasmic chaperone FK506 binding protein 5. We show that Raf1-tr has increased binding to DNA-dependent protein kinase (DNA-PK), which inhibits DNA-PK function and causes amplification of irradiation- and bleomycin-induced DNA damage. We found that the human colorectal cancer cell line, HCT-116, displayed reduced expression of Raf1-tr, and reintroduction of Raf1-tr sensitized the cells to bleomycin-induced apoptosis. Furthermore, we identified differential Raf1-tr expression in breast cancer cell lines and showed that breast cancer cells with increased Raf1-tr expression become sensitized to bleomycin-induced apoptosis. Collectively, these results demonstrate a novel Raf1 isoform in humans that has a unique noncanonical role in regulating the double-stranded DNA damage response pathway through modulation of DNA-PK function.-Nixon, B. R., Sebag, S. C., Glennon, M. S., Hall, E. J., Kounlavong, E. S., Freeman, M. L., Becker, J. R. Nuclear localized Raf1 isoform alters DNA-dependent protein kinase activity and the DNA damage response. |
| Databáze: | OpenAIRE |
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