The Moleculara Biology of Cellular Injury

The major focus of this research group is the study of responses to genotoxic stress, as well as oncogenic stresses, in mammalian cells. Genotoxic stress and other adverse environmental conditions elicit a variety of stress-related signals that lead to the altered expression of multiple genes involved in cell-cycle control, programmed cell death, and DNA repair. Interestingly, key growth-control genes, such as the tumor suppressors p53 and RB, play central roles in some of these signaling pathways, and perturbations in their function in many human tumor cells have important implications in both carcinogenesis, radiobiology, and experimental cancer treatment.

Scientific contributions include an early role in the development of sensitive assays to monitor DNA damage and repair in mammalian cells, and more recently the identification and characterization of mammalian stress response genes including the discovery of some of first mammalian DNA-damage inducible genes. The Fornace laboratory is well known for the discovery and cloning of the gadd (growth arrest and DNA damage inducible) genes and the finding that radiation-induction of the Gadd45a gene is dependent on the tumor suppressor 53 and the ATM gene product. The laboratory was the first to demonstrate regulation of a stress gene, Gadd45a, by p53 and contributed to the elucidation of the key role for the p53 signaling pathway in the maintenance of genomic stability. Recent projects have focused on stress signaling and cellular responses to radiation and chemical damage including checkpoint activation, apoptosis, and DNA repair. Dr. Fornace's laboratory has shown critical roles for the p38 MAP kinase family as a tumor suppressor and interplay between various key signaling pathways such as p53, MAP kinase, Rb, and others. These projects involve a variety of novel mouse models including gene disruption (knockout) and site-directed mutation (knockin) strategies with relevance to T-cell lymphoma, mammary cancer, skin cancer, and lung cancer.

Considering the complexity of genotoxic stress responses, another major focus has been the development of functional genomics and metabolomics approaches to monitor for stress responses at the genome-wide level. With support from the DOE Low-Dose Radiation Research Program and in collaboration with NHGRI and the Translational Genetics Institute (TGen), a stress signaling functional genomics program has been developed. Studies using microarray analysis of ionizing radiation treated cell lines have led to the identification of new p53-regulated genes and also dose-rate dependent gene responses. This approach was extended to human peripheral blood lymphocytes irradiated ex vivo and to blood from patients undergoing radiotherapy. Microarray analysis with human cells have been employed to define gene expression profiles in response to a diverse set of genotoxic and non-genotoxic stress agents. Our results to date indicate that signatures of gene expression will have utility in biodosimetry of radiation exposures and in the emerging field of toxicogenomics. Laboratory studies have implications for homeland security monitoring of exposure to toxic agents, as well as for the toxicologic assessment of new pharmaceutical agents.