Oncogenes with potential nuclear function: myc, myb and fos

Abstract

The protein products of the retroviral oncogenes, v-myc, v-myb and v-fos, and their normal cellular counterparts, the c-myc, c-myb and c-fos proto-oncogenes, have been found to be localized predominantly in the nucleus. In view of the oncogenicity of the retroviral forms of these genes, it is probable that they have central roles in the nuclear events involved in cellular proliferation and differentiation. To investigate these possibilities, detailed studies on the expression of these 'nuclear oncogenes' have been performed. The cellular forms of all three genes are normally expressed in a variety of cell types during proliferation and have RNA and protein products with short half-lives, which is consistent with the idea that they may have regulatory roles. Studies have shown that both c-myc and c-fos are induced during the stimulation of quiescent cells to enter the cell cycle and are continually expressed in replicating cells. In contrast, c-myb levels are greatest in cells as they prepare to enter and traverse S phase. Both c-myc and c-myb expression cease as cells terminally differentiate, whereas in some cell types c-fos is induced during differentiation. Unregulated expression of all three genes has distinct effects on cellular differentiation: myc seems to inhibit differentiation of several cell types when expressed at high levels; myb does not appear to effect differentiation in the systems in which it has been examined; and fos appears to be able to induce differentiation of some cell types. In most cell types, c-myc and c-myb expression is controlled primarily by posttranscriptional mechanisms, whereas c-fos expression is regulated primarily at the transcriptional level. The protein products of these oncogenes are all phosphorylated and probably undergo additional modifications. The nuclear association of these proteins is complex and apparently takes multiple forms. Taken together, these data suggest that all three nuclear oncogenes have distinct regulatory functions with respect to cellular proliferation and differentiation. Several models for function are discussed.