We are especially interested in the importance of dysregulated programmed cell death in the development of both spontaneous and radiation-induced neoplasia. We use genetically-defined models to assess the impact of disrupted programmed cell death on DNA repair pathways, mutagenesis, and genomic instability.

Programmed cell death (or apoptosis) is a fundamental property of multicellular organisms that ensures normal development and limits carcinogenesis. It is a tightly regulated process controlled by a series of proteins that include members of the BCL-2 family and the tumor suppressor protein TP53. Effector molecules (e.g. caspases and cytochrome c), carry out the process of apoptosis once it is triggered by diverse stimuli including irradiation or the withdrawl of growth factors.

Our goal is to understand the interrelationships between aberrant programmed cell death, mutagenesis, and genomic instability in human cells -- processes that are implicated in carcinogenesis. We developed isogenic human cell lines that differ only in their expression of proteins that block apoptosis (BCL-2 and BCL-XL), and showed that suppression of apoptosis led to an increased frequency of both spontaneous and x-ray-induced mutations (Cherbonnel-Lasserre, Gauny, and Kronenberg, 1996). We are dissecting the molecular mechanisms of mutagenesis, and observe a variety of spontaneous and radiation-induced changes, including point mutation, deletion, and allelic recombination -- all of which are found in human cancers.

Tight control of chromosome number and chromosomal integrity are also fundamental properties of normal human cells. The multiple genetic events needed to transform a normal human cell into a tumor cell are facilitated if the restraints on genomic stability are relaxed. We are studying the incidence of genomic instability in human cells exposed to low doses of radiation, as measured by the delayed appearance of non-clonal chromosome aberrations and elevated mutation rates.

An important aspect of our ongoing research is assessment of the impact on human cells from exposure to the unusual types of radiations found in outer space. We use different charged particles to understand how the physical pattern of energy deposition affects the frequencies and types of mutations produced. These studies are useful to NASA as they quantify the risks of human exposure during long term spaceflight (Blakely and Kronenberg, 1998). We also assess the impact of genetic variation on the response to charged particle radiations, using isogenic cell lines that differ in their expression of tumor suppressor genes and anti-apoptotic genes. These studies will help define the range of variation in individual responses to the space radiation environment.