Changes in c-Myb activity during proliferation

c-myb encodes a transcription factor and is the cellular parent of the v-myb oncogene, which causes acute myeloid leukemia in chickens and mice. Truncation or deletion can unmask the oncogenic potential of the human c-myb gene and recent reports have established that the human c-myb locus is subject to translocation and duplication in human pediatric T-ALL. c-Myb is expressed in all proliferating hematopoietic progenitor cells and has been implicated in some solid tumors, such as breast and colon. Evidence suggests that c-Myb activity is cell type specific and cell cycle dependent. For example, c-Myb interacts with cyclin D1 and CDK6 in Jurkat T-cells and this interaction inhibits c-Myb activity. Furthermore, there are numerous versions of Myb within a cell, each of which has a conserved DNA binding domain, but regulates different sets of endogenous genes. So it seems activity and specificity are regulated by domains outside of the DNA binding domain and possibly in a cell cycle-dependent manner. We hypothesized that protein interactions and post-translational modifications affect c-Myb activity in a proliferation dependent manner. We combined two model cell lines, MCF-7 cells and Jurkat T-cells, to characterize c-Myb specificity in different populations of proliferating cells. We found that c-Myb protein dynamically repositions from one gene to the next in different phases of the cell cycle. Furthermore, mitotic signals such as estrogen stimulation, affect the detection of conserved domains in the c-Myb proteins suggesting that protein interactions change while c-Myb is bound to target genes. We conclude that c-Myb activity and specificity are regulated by dynamic oscillations in binding and in the event that c-Myb itself does not reposition its binding, partners come and go to its affect activity.National Institutes of HealthBiomedical SciencesDoctoralUniversity of New Mexico. Biomedical Sciences Graduate ProgramNess, ScottOsley, Mary AnnPeabody, DaveHartley, Rebecc