A bioinformatics approach to the understanding of c-Myc biology.

摘要

c-Myc is an oncogenic transcription factor that is deregulated in many human cancers. It is a broad and weak transcription factor, regulating the expression of 15-20% of the transcriptome by 1.5-2 fold, with expression changes occurring in both directions. Our aim is to identify the biological processes and pathways regulated by c-Myc, and to identify transcription factors that mediate its transrepression activity, which is critical for c-Myc's transformation potential, and hence its oncogenicity. We approached this by first compiling a relatively comprehensive list of c-Myc-regulated genes by inducing c-Myc activity in a well-characterized c-Myc null rat fibroblast cell line, followed by microarray analysis of the transcriptome. The experiment was performed with hourly analysis for the first 6 h and well-distributed time points over 24 h. Twenty percent of the genes on the array were regulated by c-Myc, with 1,821 upregulated genes and 2,358 downregulated genes. Functional classification of the regulated genes identified many biological processes and pathways that have been previously reported. In addition, we also observed that many signaling pathways were enriched in c-Myc downregulated genes. Manual verification showed that c-Myc dampened the JAK-STAT pathway, possibly rendering the cell unresponsive to external growth signals. c-Myc also downregulated a significant number of mitotic genes, and potentially inhibits mitosis. Mitochondrial biogenesis was enriched in upregulated genes, however components in the oxidative phosphorylation pathway were not upregulated. The fine temporal resolution of the c-Myc-regulated genes immediately after c-Myc induction allowed us to set a temporal cutoff for selecting c-Myc direct target genes. We were able to perform a promoter scan of the downregulated gene promoters and identify 2 novel putative transcription factors, Myeloid zinc finger 1 and Ras responsive element binding protein 1, that potentially interact directly with c-Myc and mediate its transrepression activities. Both are anti-proliferative and pro-differentiation; disruption of their transactivation activity by c-Myc will have the opposite effect, which corresponds with c-Myc biological functions.