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Molecular and Cellular Biology, June 2006, p. 4226-4239, Vol. 26, No. 11
0270-7306/06/$08.00+0     doi:10.1128/MCB.01959-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

A Conserved Myc Protein Domain, MBIV, Regulates DNA Binding, Apoptosis, Transformation, and G2 Arrest{dagger}

Victoria H. Cowling,1,2 Sanjay Chandriani,3 Michael L. Whitfield,2 and Michael D. Cole1,2*

Departments of Pharmacology,1 Genetics, Norris Cotton Cancer Center, Dartmouth Medical School, One Medical Center Drive, Lebanon, New Hampshire 03756,2 Department of Molecular Biology, Princeton University, Princeton, New Jersey 085403

Received 6 October 2005/ Returned for modification 12 December 2005/ Accepted 12 March 2006

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, Myc{Delta}MBIV 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-Myc{Delta}MBIV reveals that it is weakened for transactivation and repression but not nearly as defective as N-Myc{Delta}MBII. Although the mutated region is not part of the previously defined DNA binding domain, we find that N-Myc{Delta}MBIV has a significantly lower affinity for DNA than the wild-type protein in vitro. Furthermore, chromatin immunoprecipitation shows reduced binding of N-Myc{Delta}MBIV 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.

* Corresponding author. Mailing address: Department of Pharmacology, Norris Cotton Cancer Center, Dartmouth Medical School, One Medical Center Drive, Lebanon, NH 03756. Phone: (603) 653-9975. Fax: (603) 653-9952. E-mail: mcole{at}dartmouth.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, June 2006, p. 4226-4239, Vol. 26, No. 11
0270-7306/06/$08.00+0     doi:10.1128/MCB.01959-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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