Transcriptional repression: the dark side of myc.

The (c-)Myc oncoprotein and its cousins, the N-Myc and L-Myc proteins, show all hallmarks of transcriptional activator proteins: Myc carries a carboxy-terminal DNA binding domain, which mediates sequence-specific binding to DNA. At its amino-terminus, Myc carries a transcriptional regulatory domain that strongly activates transcription when fused to an ectopic DNA binding domain; moreover, the strength of activation of different members of the Myc family correlates with their ability to transform rodent cells. Furthermore, activation of conditional alleles of Myc, either tetracycline or estrogen inducible, upregulates expression of a large number of genes, both in tissue culture and in transgenic animals. Indeed, many of these genes have essential roles in cell proliferation, cell growth, and metabolism; two of them, odc, encoding ornithine decarboxylase, a rate-limiting enzyme of polyamine biosynthesis, and rpl24, encoding a constituent of the large ribosomal subunit, are haploinsufficient for Myc-induced lymphomagenesis but not for normal development, arguing very strongly that upregulation of both genes is critical for Myc-dependent tumor formation. Undoubtedly, therefore, Myc exerts part of its biological activities via transcriptional upregulation of a large number of target genes. One of the key issues in the field is whether there are additional biochemical activities of the Myc protein and, if so, whether and how they contribute to Myc biology. This review summarizes evidence demonstrating that Myc has the ability to repress transcription and that this may be an important function during oncogenic transformation.