INVESTIGATING THE ROLE AND REGULATION OF THE SPECIFIC ANDGENERAL PRB-E2F1 INTERACTIONS

Abstract

Background/Purpose. The retinoblastoma tumor suppressor protein (pRB) plays a central role in proliferative control and is a frequent target for inactivation in cancer. The G1-Sphase transition of the cell cycle is regulated by pRB, which is capable of interacting with E2F family members and inhibiting the transcription of genesrequired to progress into S-phase. E2F1 is unique from other E2F family members as it can induce both apoptosis and proliferation. To control these contrasting functions of E2F1, a second E2F1 binding site exists in the C-terminus of pRB that can control apoptosis separately from proliferation. This anti-apoptotic function of pRBcan in some circumstances promote tumorigenesis, which leads to the question; is pRB a tumor suppressor or an oncogene? Methods. To investigate this, a gene-targeted mouse model is being engineered to selectively disrupt the ability of pRB to control proliferation through the general E2F binding site while still retaining the ability tocontrol apoptosis through the specific E2F1 site. Results. A series of novel mutants were engineered to selectively disrupt the binding of E2Fs at the general site, and prevent pRB from controlling proliferation. The mutants retain the ability to bind E2F1 and control apoptosis through thespecific binding site, which is not disrupted. Conclusions. By separating the ability of pRB to control proliferation and apoptosis under in vivo conditions, a better understanding into the significance of these two functions in development and tumorigenesis can be gained.