Differential oncogenic potential of activated RAS isoforms in melanocytes
| Autor: | James H. Resau, Matthew W. VanBrocklin, Bilgili D, Haak Pt, Whitwam T, Han Mo Koo, Sheri L. Holmen, Russo Me |
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| Rok vydání: | 2007 |
| Předmět: |
Neuroblastoma RAS viral oncogene homolog
Cancer Research Mutant Biology medicine.disease_cause Proto-Oncogene Proteins c-myc Cell Line Tumor Tumor Suppressor Protein p14ARF Genetics medicine Humans Protein Isoforms HRAS Melanoma neoplasms Molecular Biology Cyclin-Dependent Kinase Inhibitor p16 Cell Proliferation Mutation medicine.disease Molecular biology Cell Transformation Neoplastic Genes ras Melanocytes KRAS Carcinogenesis Melanocyte proliferation |
| Zdroj: | Oncogene. 26:4563-4570 |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/sj.onc.1210239 |
| Popis: | RAS genes are mutated in approximately 30% of all human cancers. Interestingly, there exists a strong bias in favor of mutation of only one of the three major RAS genes in tumors of different cellular origins. NRAS mutations occur in approximately 20% of human melanomas, whereas HRAS and KRAS mutations are rare in this disease. To define the mechanism(s) responsible for this preference in melanocytes, we compared the transformation efficiencies of mutant NRAS and KRAS in immortal, non-transformed Ink4a/Arf-deficient melanocytes. NRAS mutation leads to increased cellular proliferation and is potently tumorigenic. In contrast, KRAS mutation does not enhance melanocyte proliferation and is only weakly tumorigenic on its own. Although both NRAS and KRAS activate mitogen-activated protein kinase signaling, only NRAS enhances MYC activity in these cells. Our data suggest that the activity of specific RAS isoforms is context-dependent and provide a possible explanation for the prevalence of NRAS mutations in melanoma. In addition, understanding this mechanism will have important implications for cancer therapies targeting RAS pathways. |
| Databáze: | OpenAIRE |
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