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Abstract
The myc family of oncogenes is well conserved throughout evolution. Here we present the characterization of a domain conserved in c-, N-, and L-Myc from fish to humans, N-Myc317-337, designated Myc box IV (MBIV). A deletion of this domain leads to a defect in Myc-induced apoptosis and in some transformation assays but not in cell proliferation. Unlike other Myc mutants, MycΔMBIV is not a simple loss-of-function mutant because it is hyperactive for G2 arrest in primary cells. Microarray analysis of genes regulated by N-MycΔMBIV reveals that it is weakened for transactivation and repression but not nearly as defective as N-MycΔMBII. Although the mutated region is not part of the previously defined DNA binding domain, we find that N-MycΔMBIV has a significantly lower affinity for DNA than the wild-type protein in vitro. Furthermore, chromatin immunoprecipitation shows reduced binding of N-MycΔMBIV to some target genes in vivo, which correlates with the defect in transactivation. Thus, this conserved domain has an unexpected role in Myc DNA binding activity. These data also provide a novel separation of Myc functions linked to the modulation of DNA binding activity.
Supplemental material for this article may be found at http://mcb.asm.org/.
We thank Iulia Kotenko and Ruth Kilburn for technical assistance and Steve Fiering for providing valuable resources. We also thank the members of the Cole lab for input into the manuscript.
This work was supported by a grant from the National Cancer Institute to M.D.C. M.L.W. was supported by Howard Hughes Medical Institute Biomedical Research Support Award 76200-560801 to Dartmouth College, American Cancer Society Institutional Award IRG-82-003-17 to the Norris Cotton Cancer Center, and a grant from the V Foundation for Cancer Research. M.L.W. is a V Scholar of the V Foundation for Cancer Research.