Deregulation of common genes by c-Myc and its direct target, MT-MC1.

Abstract

In addition to its role in cancer, the c-Myc oncoprotein controls many normal cellular processes as a consequence of its function as a basic helix-loop-helix leucine zipper transcription factor. Determining which of the myriad genes under c-Myc control are relevant for these various roles is thus a major challenge. mt-mc1 is a direct c-Myc target gene whose overexpression recapitulates multiple c-Myc phenotypes, including transformation. Using transcriptional profiling, we now show that MT-MC1-overexpressing myeloid cells misregulate a total of 47 distinct transcripts, a large proportion of which are involved in signal transduction and/or cancer. Analysis of these genes reveals a consensus promoter structure consisting of multiple, often closely spaced c-Myc binding sites and three additional Wilm's tumor and Egr1-like motifs. More than one-third of MT-MC1 target genes are also clustered on six cancer-associated chromosomal loci. Most surprisingly, all of the transcripts examined also are regulated by c-Myc. Finally, an estrogen receptor-MT-MC1 fusion protein was used to establish that all examined transcripts were regulated directly by the chimeric protein. Our results thus indicate that MT-MC1 target genes largely comprise a subset of those regulated by c-Myc. We propose that the properties imparted by MT-MC1 are the result of its control of a small and select c-Myc target gene population.