Expression of c-cbl proto-oncogene is modulated during differentiation but not during induction of proliferation

The proto-oncogene c-cbl is expressed as two mRNAs, ca. 10.5 and 3.1 kb, both of which appear to be functional inasmuch as both can be found on polyribosomes in tissues that express both mRNAs. The function of the 120 kDa c-cbl protein is not known, but its primary structure resembles that of a DNA-binding transcription factor with a basic region, a nuclear localization sequence, a zinc finger-like motif and a leucine zipper. To test whether expression of this protein resembles that of regulatory proteins, we studied expression of c-cbl mRNA and protein in differentiating cells and in proliferating cells, conditions in which expression of regulatory proteins commonly is modulated. Differentiation of both erythroleukemia cells and teratocarcinoma cells showed a decrease in c-cbl expression, with kinetics similar to those of transcription factors that are immediate early response genes. Unlike early response genes, however, c-cbl mRNA showed a very long half life in B lymphocytes. Further, in fibroblasts and spleen cells that were induced to proliferate, c-cbl mRNA expression did not change, and expression of c-cbl protein did not change during any stage of the cell cycle. These characteristics indicate that c-cbl does not belong to the immediate early response type of transcription factor. Yet when c-cbl is truncated, as in v-cbl, the protein does enter the nucleus and bind DNA, and it contributes to neoplastic transformation of B lymphocytes and fibroblasts. These findings indicate that the regulation of the c-cbl proto-oncogene is different from that of the proto-oncogenes identified to date and suggest that c-cbl belongs to a new class of proto-oncogenes.