c-Myb trans-Activates the Human DNA Topoisomerase IIα Gene Promoter

DNA topoisomerase IIα (topo IIα) is an essential proliferation-dependent nuclear enzyme which has been exploited as an anti-tumor drug target. Since the proliferative status of human leukemia cells is associated with expression of the c- myb proto-oncogene, c-Myb was investigated as a trans -activator of the topo IIα gene. Using topo IIα promoter-luciferase reporter plasmids, c- myb expression caused trans -activation of the topo IIα promoter a maximum of ∼4.5-fold over basal levels in HL-60 human promyelocytic leukemia cells. Trans -activation was submaximal with higher levels of c- myb expression plasmid but a Myb protein lacking its negative regulatory domain resulted in ∼19-fold trans -activation. Mutagenesis and 5′-deletion studies revealed that Myb trans -activation was mediated via a Myb-binding site at positions −16 to −11 and that this region governed the bulk of basal topo IIα promoter activity in human leukemia cells. Trans -activation of topo IIα by c-Myb was lymphoid- or myeloid-dependent. However, B-Myb, a more widely-expressed Myb family member, caused topo IIα trans -activation in both HL-60 cells and HeLa epithelial cervical carcinoma cells. These data provide evidence for a new Myb-responsive gene which is directly linked to and required for cellular proliferation.