Physiological function as regulation of large transcriptional programs: the cellular response to genotoxic stress

The responses to ionizing radiation and other genotoxic environmental stres ses are complex and are regulated by a number of overlapping molecular path ways. One such stress signaling pathway involves p53, which regulates the e xpression of over 100 genes already identified. It is also becoming increas ingly apparent that the pattern of stress gene expression has some cell typ e specificity. It may be possible to exploit these differences in stress ge ne responsiveness as molecular markers through the use of a combined inform atics and functional genomics approach. The techniques of microarray analys is potentially offer the opportunity to monitor changes in gene expression across the entire set of expressed genes in a cell or organism. As an initi al step in the development of a functional genomics approach to stress gene analysis, we have recently demonstrated the utility of cDNA microarray hyb ridization to measure radiation-stress gene responses and identified a numb er of previously unknown radiation-regulated genes. The responses of some o f these genes to DNA-damaging agents vary, widely in cell lines from differ ent tissues of origin and different genetic backgrounds. While this again h ighlights the importance of a cellular context to genotoxic stress response s, it also raises the prospect of expression-profiling of cell lines, tissu es, and tumors. Such profiles may have a predictive value if they can defin e regions of expression space' that correlate with important endpoints, suc h as response to cancer therapy regimens, or identification of exposures to environmental toxins. Published by Elsevier Science Inc.