Oxidative stress and DNA damage play a critical role in the development of degenerative diseases, and may underlie the aging process itself. Cells respond to such stresses with the induction of numerous gene products but little is known concerning the signal transduction pathways mediating these effects or the functional significance of the induced gene products. This project encompasses several areas related to these cellular responses. Studies are devoted to understanding basic mechanisms associated with the genetic responses to DNA damage and oxidative stress. We have utilized the growth arrest and DNA damage inducible gene, GADD153, as a model to investigate the signal transduction pathways operating to regulate gene expression following DNA damage. Evidence has accumulated from other laboratories to support the existence of at least two distinct pathways operating to enhance gene expression following different types of DNA damaging treatments. One is dependent on the tumor suppressor gene product p53, and appears to be limited to X-ray damage and a small subset of genes. The second, which appears to be a more universal response, is p53 independent, relies on the activation of tyrosine kinases and involves c-ras, c-raf, and ERKs. We have obtained evidence to suggest that GADD153 is activated through a p53-independent pathway which does not require activation of tyrosine kinases and is independent of c-ras and c-raf activation. However, recent evidence suggests that an alternative pathway dependent on p53 could also contribute to GADD153 induction in response to DNA damage. A second area of focus in this project is the investigation of the response to DNA damage as a function of aging. These experiments thus far have relied on in vitro senescence of fibroblasts as a model of aging. We have obtained preliminary evidence to indicate that at least one subset of genes whose expression is dependent on certain AP-1 transcription factors declines with in vitro aging.
