C/EBPβ deletion in oncogenic Ras skin tumors is a synthetic lethal event
| العنوان: | C/EBPβ deletion in oncogenic Ras skin tumors is a synthetic lethal event |
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| المؤلفون: | Zachary J. Messenger, Robert C. Smart, John S. House, Jonathan R. Hall, Debra A. Tokarz, Hann W. Tam, Dereje D. Jima |
| المصدر: | Cell Death & Disease Cell Death and Disease, Vol 9, Iss 11, Pp 1-16 (2018) |
| بيانات النشر: | Nature Publishing Group UK, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Keratinocytes, Cancer Research, Skin Neoplasms, DNA damage, Cellular differentiation, 9,10-Dimethyl-1,2-benzanthracene, Immunology, Apoptosis, Synthetic lethality, Biology, medicine.disease_cause, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Mice, medicine, Animals, lcsh:QH573-671, Transcription factor, Skin, Mice, Knockout, lcsh:Cytology, CCAAT-Enhancer-Binding Protein-beta, Cancer, Cell Differentiation, Cell Biology, Receptors, Death Domain, medicine.disease, 3. Good health, Gene Expression Regulation, Neoplastic, 030104 developmental biology, Cell Transformation, Neoplastic, Cancer research, ras Proteins, Tetradecanoylphorbol Acetate, Genes, Lethal, Signal transduction, Tumor Suppressor Protein p53, Carcinogenesis, Signal Transduction |
| الوصف: | Therapeutic targeting of specific genetic changes in cancer has proven to be an effective therapy and the concept of synthetic lethality has emerged. CCAAT/enhancer-binding protein-β (C/EBPβ), a basic leucine zipper transcription factor, has important roles in cellular processes including differentiation, inflammation, survival, and energy metabolism. Using a genetically engineered mouse model, we report that the deletion C/EBPβ in pre-existing oncogenic Ha-Ras mouse skin tumors in vivo resulted in rapid tumor regression. Regressing tumors exhibited elevated levels of apoptosis and p53 protein/activity, while adjacent C/EBPβ-deleted skin did not. These results indicate that the deletion of C/EBPβ de-represses p53 in oncogenic Ras tumors but not in normal wild-type Ras keratinocytes, and that C/EBPβ is essential for survival of oncogenic Ras tumors. Co-deletion of C/EBPβ and p53 in oncogenic Ras tumors showed p53 is required for tumor regression and elevated apoptosis. In tumors, loss of a pathway that confers adaptability to a stress phenotype of cancer/tumorigenesis, such as DNA damage, could result in selective tumor cell killing. Our results show that oncogenic Ras tumors display a significant DNA damage/replicative stress phenotype and these tumors have acquired a dependence on C/EBPβ for their survival. RNAseq data analysis of regressing tumors deleted of C/EBPβ indicates a novel interface between p53, type-1 interferon response, and death receptor pathways, which function in concert to produce activation of extrinsic apoptosis pathways. In summary, the deletion of C/EBPβ in oncogenic Ras skin tumors is a synthetic lethal event, making it a promising target for future potential anticancer therapies. |
| اللغة: | English |
| تدمد: | 2041-4889 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::af2ad7aba723d2bf4acf81718a01f0eeTest http://europepmc.org/articles/PMC6189130Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....af2ad7aba723d2bf4acf81718a01f0ee |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20414889 |
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