1. Activation of K-RAS by co-mutation of codons 19 and 20 is transforming
- Author
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Mark J. Arends, David J. Adams, Catherine H. Wilson, and Adam Naguib
- Subjects
Genetics ,MAPK/ERK pathway ,0303 health sciences ,Mutation ,Oncogene ,Cell division ,Mutant ,Cell Biology ,Biology ,medicine.disease_cause ,Biochemistry ,Molecular biology ,3. Good health ,03 medical and health sciences ,Transformation (genetics) ,0302 clinical medicine ,030220 oncology & carcinogenesis ,medicine ,Molecular Biology ,Protein kinase B ,PI3K/AKT/mTOR pathway ,030304 developmental biology - Abstract
The K-RAS oncogene is widely mutated in human cancers. Activating mutations in K-RAS give rise to constitutive signalling through the MAPK/ERK and PI3K/AKT pathways promoting increased cell division, reduced apoptosis and transformation. The majority of activating mutations in K-RAS are located in codons 12 and 13. In a human colorectal cancer we identified a novel K-RAS co-mutation that altered codons 19 and 20 resulting in transitions at both codons (L19F/T20A) in the same allele. Using focus forming transformation assays in vitro , we showed that co-mutation of L19F/T20A in K-RAS demonstrated intermediate transforming ability that was greater than that of individual L19F and T20A mutants, but less than that of G12D and G12V K-RAS mutants. This demonstrated the synergistic effects of co-mutation of codons 19 and 20 and illustrated that co-mutation of these codons is functionally significant.
- Published
- 2011