1999 Publication

Molecular responses to genotoxic stress are complex and are mediated by a variety of regulatory pathways. One key element in cellular response is the stress gene transcription factor p53, which can regulate nearly 100 genes that have already been identified. Although p53 plays a central role in the cellular response to DNA-damaging agents such as ionizing radiation (IR), other pathways can also have important roles. One example is the transcriptional responses associated with IR-induced apoptosis, where induction of some genes is limited to p53 wild-type (wt) cells that also have the ability to undergo rapid apoptosis after irradiation. In contrast, other genes are triggered after IR in lines undergoing rapid apoptosis regardless of p53 status. From this and other examples, it is apparent that the pattern of stress gene expression is cell type specific in both primary and transformed lines. The premise will be developed that such differences in stress gene responsiveness can be employed as molecular markers using a combination of informatics and functional genomics approaches. An example is given using the panel of lines of the NCI anticancer drug screen where both the p53 status and sensitivity to a large collection of cytotoxic agents have been determined. The utility of cDNA microarray hybridization to measure IR-stress gene responses has recently been demonstrated and a large number of additional IR-stress genes have been identified. The responses of some of these genes to IR and other DNA-damaging agents varied widely in cell lines from different tissues of origin and different genetic backgrounds, highlighting the importance of cellular context to genotoxic stress responses; this also highlights the need for informatics approaches to discover and prioritize hypotheses regarding the importance of particular cellular factors. The aim of this review is to demonstrate the utility of combining an informatics approach with functional genomics in the study of stress responses.