Activation of murine c-abl protooncogene: effect of a point mutation on oncogenic activation

• Published in: Proceedings of the National Academy of Sciences - PNAS 1990-09, Vol.87 (17), p.6502-6506
• Main Authors: Shore, S K, Bogart, S L, Reddy, E P
• Format: Article
• Language: English
• Subjects: Abelson murine leukemia virus - genetics; Animals; Cell Line; Cell Transformation, Neoplastic; Chromosome Deletion; Gene Expression Regulation; Genetic Vectors; Hardy-Zuckerman feline sarcoma virus; Leukemia Virus, Murine - genetics; Mice; Mutation; Plasmids; Protein-Tyrosine Kinases - genetics; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins c-abl; Proto-Oncogenes; Transfection
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.87.17.6502

Activation of the c-abl protooncogene occurs in Abelson murine leukemia virus, in Hardy-Zuckerman 2 feline sarcoma virus, and during the chromosomal translocations that generate BCR-ABL gene fusion products. To study the molecular mechanism involved in the c-abl activation, we have created a series of modifications in murine c-abl and assayed these constructs for oncogenic activity using the NIH 3T3 cell transformation assay. Our results show that amino-terminal deletions are sufficient for oncogenic activation of c-abl and high levels of oncogenic activities were generated by a deletion of 114 codons from the 5' end that deleted the SH3 region. A deletion of 53 codons from the 5' end (inclusive of deletions seen in Hardy-Zuckerman 2 feline sarcoma virus and BCR-ABL gene products) that retains the SH3 region of c-abl resulted in the generation of low levels of transforming activity. This transforming potential was substantially increased with the introduction of a G---A point mutation in codon 832 that is present in v-abl. The point mutation was found to affect the secondary structure and the tyrosine kinase activity of the mutant gene products.