Identification of Myc-mediated death response pathways by microarray analysis.
To understand the mechanisms of Myc-mediated apoptosis induced by DNA damage, we have characterized the death kinetics of three Rat-1 fibroblast cell lines that either overexpress Myc or lack Myc and their parental wild-type cells following exposure to the DNA-damaging agent VP-16, and we monitored the changes in gene expression using microarray. We have identified three groups of genes whose expressions are distinctly regulated during this process. One cluster (Cluster A) revealed a VP-16-dependent but Myc-independent induction of a set of genes that is not linked to the apoptotic response. Two other gene clusters, however, were associated with VP-16-induced apoptosis. Cluster B, which includes p53-responsive genes, was associated with the temporal onset of apoptosis but accounted for only the basal apoptosis. However, Cluster C, which includes c-jun, was highly regulated by Myc and appeared to be critical to mounting the maximal apoptotic response in Myc-expressing cells. Furthermore, the Myc level dropped sharply following VP-16 exposure, which varied inversely with the induction of Cluster C genes, suggesting Myc normally represses their transcription. Thus, we have proposed that removal of Myc-mediated repression of apoptotic signals, combined with Myc-associated acceleration of the p53 responsive pathway, results in complete and rapid cell death following DNA damage.
Yu
Qiang
Q
Advanced Technology Center, Center for Cancer Research, NCI/National Institutes of Health, Gaithersburg, MD 20877, USA.
He
Mei
M
Lee
Norman H
NH
Liu
Edison T
ET
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001483:Base Sequence; D017931:DNA Primers; D005047:Etoposide / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D016271:Proto-Oncogene Proteins c-myc; D005047:Etoposide