Abstract
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.
Highlights
One possibility is that Myc promotes cell death by sensitizing cells to other apoptotic stimuli, rather than by acting as a direct death effector (4)
The complexity of these results suggests that a genomewide survey for Myc-mediated gene expression under apoptotic conditions might allow the unbiased identification of Myc target genes responsible for its pro-apoptotic function
In Reagents—Myc wild-type fibroblast cells TGR-1 (Rat1) cells, 25% apoptosis was observed around 8 h after drug treatment, and most of the cells became apoptotic after 24 h, whereas the myc-null cells did not undergo detectable apoptotic response until 48 h after drug treatment
Summary
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. Putative Myc target genes p19 ARF 1 (8) and cyclin A (7) have been shown to be specific for mediating the apoptotic function of Myc, providing direct molecular links between Myc and the induction of apoptosis. Other transcriptional programs independent of p53 response are implicated in the DNA damage-induced apoptotic pathway (13, 14). The complexity of these results suggests that a genomewide survey for Myc-mediated gene expression under apoptotic conditions might allow the unbiased identification of Myc target genes responsible for its pro-apoptotic function. We describe the identification of Myc-mediated transcriptional programs in DNA damage-induced apoptosis. Our study identified certain gene clusters that are most linked to Mycmediated apoptosis
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