c-Myb

The c-Myb protein is a DNA-binding transcriptional regulator with a highly conserved DNA-binding domain composed of three ‘Myb repeats’ resembling consecutive homeodomain-like or helix–turn–helix-like motifs. The proto-oncoprotein c-Myb is the normal counterpart to the oncogenic v-Myb proteins expressed by two avian leukemia viruses, avian myeloblastosis virus (AMV) and E26. Both viruses induce acute myeloid leukemias in birds and transform immature myeloid cells in tissue culture. In birds and mice, the c-myb gene is a common target for retroviral insertions leading to myeloid and lymphoid tumors. Interestingly, transgenic overexpression of normal c-Myb does not induce tumors in mice, although transgenic v-Myb can induce leukemias after a long latency, indicating that v-Myb-induced leukemogenesis requires additional secondary mutations. Thus, the c-Myb protein seems to have latent transforming and leukemogenic potential that can be unleashed through various mechanisms. Mice lacking functional c-myb genes die in utero of a severe anemia, showing that c-Myb is required for definitive erythropoiesis. Inducible c-myb knockouts have shown that c-Myb is required for the development of multiple hematopoietic lineages as well as T cells. The c-Myb protein is also thought to have an important regulatory function in other cell types, especially epithelial cells. Expression of the c-myb gene is regulated during the cell cycle, indicating that it has a function in the regulation of cell-cycle-regulated genes. However, the c-Myb protein seems to regulate completely different sets of genes in different cell types, and even minor changes to the structure of c-Myb can have marked effects on its ability to regulate specific genes, indicating that the specificity of Myb proteins is controlled in a complex manner, probably through numerous protein–protein interactions.