Identifying Genes Regulated in a Myc-dependent Manner

Abstract

The c-myc proto-oncogene can direct a diverse array of biological activities, including cell cycle progression, apoptosis, and differentiation. It is believed that Myc can affect this wide variety of activities by functioning as a regulator of gene transcription, although few targets have been identified to date. To delineate the molecular program regulated downstream of Myc, we used a cDNA microarray approach and identified 52 putative targets out of >6000 cDNAs analyzed. To further distinguish the subset of genes whose regulation was dependent upon Myc per se from those regulated in response to activation of general mitogenic or apoptotic programs, the putative cDNA targets were then screened by a series of assays. By this approach 37 putative targets were ruled out and 15 Myc target genes were uncovered. Interestingly, comparing our results with other high throughput screens reveals that certain putative Myc targets previously reported are shown not to be regulated downstream of Myc (e.g. ribosomal proteins, HSP90␤), whereas others are further supported by our analyses (e.g. pdgf␤r, nucleolin). The identity of genes specifically regulated downstream of Myc provides the critical tools required to understand the role Myc holds in the transformation process and to delineate how Myc functions as a regulator of gene transcription.

Myc pathways provoking cell suicide and cancer

“…Myc target genes have been identified by a number of approaches, most recently in SAGE and microarray screens designed to capture those targets induced or repressed following conditional activation of the oncoprotein (Coller et al, 2000;Boon et al, 2001;Neiman et al, 2001;Schuldiner and Benvenisty, 2001;Godfried et al, 2002;Iritani et al, 2002;Menssen and Hermeking, 2002;Watson et al, 2002;Yu et al, 2002;Ellwood-Yen et al, 2003;Huang et al, 2003). The cast of targets is ponderous (with at least 647 targets already identified, see http://www.myc-cancer-gene.org).…”

In vivo transcriptional regulation of N-Myc target genes is controlled by E-box methylation

“…Despite the many strategies adopted to identify genes regulated by Myc proteins (13)(14)(15)(16)(17)(18)(19), a full comprehension of which genes are genuinely regulated by Myc, and how, is far from being achieved. This aspect has been also complicated by the finding that Myc appears to be associated with several DNA sites interspersed within the genomic DNA (17,19,20).…”

Dissection of transcriptional programmes in response to serum and c-Myc in a human B-cell line

“…Mycinduced cell growth and proliferation is associated with the up-and downregulation of a large number of target genes (www.myccancergene.org). Unfortunately, experiments in c-mycÀ/À rat fibroblasts revealed only few target genes to be regulated by Myc, but not by other serum-induced transcription factors (Bush et al, 1998;Watson et al, 2002). Which genes are dependent on Myc for their expression?…”