Paradoxical effects of Bax and Bcl-2 on oncogenesis

Resistance to cell death is paramount to oncogenesis and is often mediated by differential expression of anti- versus pro-apoptotic Bcl-2 family members. Despite their role in regulating apoptosis, several studies have demonstrated that Bcl-2 family members have paradoxical effects on cancer. In clinical studies of human cancers, Bcl-2 was associated with increased survival whereas the converse was associated with increased Bax expression. These observations have been extended into mouse models of cancer where cause and effect can be tested. This dissertation investigates how increased Bax expression in transgenic mice (Lck-Bax38/1) promotes T cell lymphoma. Previous studies of Lck-Bax38/1 demonstrated aneuploidy and accelerated tumor formation in both p53 +/+ and p53 -/- mice. This led us to hypothesize that Bax promotes oncogenesis by increasing chromosomal instability (CIN). To test this quantitative cytogenetic analysis was employed. Consistent with this hypothesis, thymi from young Lck-Bax38/1 mice frequently showed increased levels of aneuploidy regardless of p53 status prior to tumor formation and all thymic tumors derived from these mice were consistently aneuploid. Bcl-2 expression was able to suppress aneuploidy and tumor formation in Lck-Bax38/1 mice.;Several studies suggest the paradoxical effects of Bcl-2 family members on cancer involve regulation of cellular proliferation. Bcl-2 family regulation of cellular proliferation has been ascribed to the regulation of the cell cycle inhibitor and tumor suppressor p27. Variations in p27 gene dosage did not affect the percentage of cycling thymocytes or tumor formation in Lck-Bax38/1 mice and suggests that p27 does not function as a tumor suppressor in this mouse model.;A number of reports have linked the Bcl-2 family to alterations in reactive oxygen species (ROS). Studies linking either Bax expression or ROS production to CIN prompted us to examine the role of ROS in Bax induced lymphoma formation. Variations in MnSOD gene dosage did not affect apoptosis or cellular proliferation but significantly affected CIN in pre-malignant thymi as well as the onset of tumor formation in Lck-Bax38/1 mice. This dissertation supports a novel link between Bcl-2 family members and CIN and could account for the paradoxical effects of Bcl-2 family members on cancer.