| E2F transcriptional activity is critical for the control of cell cycle progression and apoptosis. Using E2F1 deficient mice, I show that E2F1 is important for the apoptosis of autoimmune immature T cells during thymic negative selection in vivo. This TCR mediated apoptosis coincides with E2F1-dependent increase of p19ARF mRNA and p53 protein levels. These results suggest a specific role for E2F1 in a physiological apoptosis pathway that is uncoupled from a normal proliferative event. In order to assess potential functional redundancy between E2F1 and E2F2, E2F1 and E2F2 double knock-out (DKO) mice were studied. My results indicate a novel negative regulation of cell proliferation by E2F1 and E2F2. Loss of E2F1 and E2F2 impedes B cell differentiation, and hematopoietic progenitor cells in the bone marrow of DKO mice exhibit increased cell cycling. Importantly, E2F1 and E2F2 DKO T cells exhibit a more rapid entry into S phase following antigenic stimulation. Furthermore, T cells lacking E2F1 and E2F2 proliferate much more extensively in response to subthreshold antigenic stimulation. Consistent with these observations, E2F1/E2F2 mutant mice are highly predisposed to the development of tumors, and some mice exhibit lymphocytic infiltration of organs. Unexpectedly, E2F mutant mice also show severe defects in pancreatic physiology and E2F1 and E2F2 DKO mice develop insulin-dependent diabetes, which does not require mature lymphocytes. The studies included in this thesis significantly advance our understanding of the roles for E2F1 and E2F2 in cell cycle progression and apoptosis under physiological conditions and have potential implications for the development of therapeutics for the treatment of cancer, autoimmunity and diabetes. |
