c-Maf Interacts with c-Myb To Regulate Transcription of an Early Myeloid Gene during Differentiation

ABSTRACT

The MafB transcriptional activator plays a pivotal role in regulating lineage-specific gene expression during hematopoiesis by repressing Ets-1-mediated transcription of key erythroid-specific genes in myeloid cells. To determine the effects of Maf family proteins on the transactivation of myeloid-specific genes in myeloid cells, we tested the ability of c-Maf to influence Ets-1- and c-Myb-dependentCD13/APN transcription. Expression of c-Maf in human immature myeloblastic cells inhibited CD13/APN-driven reporter gene activity (85 to 95% reduction) and required the binding of both c-Myb and Ets, but not Maf, to the promoter fragment. c-Maf’s inhibition of CD13/APN expression correlates with its ability to physically associate with c-Myb. While c-Maf mRNA and protein levels remain constant during myeloid differentiation, formation of inhibitory Myb-Maf complexes was developmentally regulated, with their levels being highest in immature myeloid cell lines and markedly decreased in cell lines representing later developmental stages. This pattern matched that of CD13/APNreporter gene expression, indicating that Maf modulation of c-Myb activity may be an important mechanism for the control of gene transcription during hematopoietic cell development.

ACKNOWLEDGMENTS

We thank Elizabeth Mann for expert technical assistance, Rick Bram, David Shapiro, John Cleveland, and Paul Brindle for helpful comments, H. P. Koeffler for his gift of myeloid cell lines, Barbara Graves for her gift of ETS-1 plasmids, and John Gilbert for editorial assistance.

This study was supported by NIH grant CA-70909 to L.H.S., by National Cancer Institute Cancer Center Support (CORE) grant CA-21765, and by the American Lebanese Syrian Associated Charities, St. Jude Children’s Research Hospital.