The development of neoplasms in vertebrates is often associated with alterations in the structure or expression of cellular proto-oncogenes. We have isolated, cloned and sequenced an oncogene, v-cbl, that was captured by a retrovirus that induces pre-B cell lymphomas in vivo. Cellular sequences related to v-Cbl map to mouse chromosomes 6 (Cbl-1) and 9 (Cbl-2) and to human chromosome 11. Studies of human neoplasms carrying various translocations of chromosome 11 have mapped the cbl gene to llq23 in close linkage to the THY1 and ETS1 loci. We have isolated genomic and cDNA clones of cbl and are sequencing these clones to determine the structure of the CBL gene in normal cells. The Cbl-1 gene is a pseudogene containing many mutations with respect to the cbl cDNA sequence and it was inserted into a LINE element. Sequencing of the Cbl-2 locus shows this gene to have a complex organization since the exons are small (88-250 nucleotides) and size of the mRNA is quite large with 2 predominant mRNA species of 11 and 3.7 kb. Cbl mRNA was found to be transcribed in resting fibroblasts and was not inducible in response to various stimuli. Studies with antibodies against v-cbl show cbl to be a nuclear protein. In addition, cbl is homologous to GCN4, a yeast transcription activation factor, in its DNA binding and transactivation regions. These data suggest that cbl may also be a DNA binding transcription factor. Further studies will be directed at completing the sequence of the Cbl-2 germline gene to elucidate its structure, and to determine the 5' regulatory region of the gene to evaluate which transcription factors play a role in cbl expression.
