REGULATION OF CELL PROLIFERATION BY GENES OF THE MYB FAMILY

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The objective of this proposal is to assess the relative contribution of the genes of the myb family (A-myb, B-myb and c-myb) to the regulation of cell proliferation in hematopoietic and non-hematopoietic cells. Preliminary evidence suggests that B-myb is a c-myb equivalent in non-hematopoietic cells, although B-myb and c-myb may transactivate different genes, or differ in the potency of their transactivating domains or in the affinity to myb binding sites in the same target genes. The role of A-myb is less understood; in certain tumor lines it appears to negatively regulate colony formation, perhaps by antagonizing the activity of c-myb and/or B-myb via interaction with Myb binding sites of Myb (c-myb and/or B-myb)-regulated genes or by activating genes involved in negative regulation of cell growth. However, ectopic A-myb expression in fibroblasts accelerates cell cycle progression, raising the possibility that: I) A-myb exerts distinct functions in different cell types; or ii) the consequences of A-myb activity are different in different cell types. By dissecting differences in the activity of A-myb, B-myb and c-myb, the proposed studies 1) will reveal mechanisms of cell proliferation control in which genes of the same family play complementary or competing roles; and 2) might provide the rationale for novel therapeutic interventions based on suppressing the activity of genes of the Myb family.