The disruption of various components of the pathway controlling E2F accumulation, either the activation of positive acting components such as the G1 cyclins or the inactivation of negative components such as Rb and the cdk inhibitors, can lead to the loss of cell growth control underlying the development of various forms of human cancer. Mammalian E2F is composed of a family of heterodimers encoded by distinct genes. Each E2F protein appears to activate a distinct set of target genes and E2F uniquely induces apoptosis. In addition, recent studies describing the consequences of the disruption of the E2F1 gene in the mouse suggest a role for E2F1 in the induction of apoptosis in the physiological context of thymocyte maturation. Given the importance of E2F in the control of proliferation and cell fate, it is critical that we understand the mechanism underlying transcriptional specificity of the different E2F family members which contributes to their specific roles. The proposed studies will be directed at understanding the role of the E2F transcription factor family in cell growth and cell fate determination. These studies will involve four specific aims: 1) the identification of the specific genes regulated by the individual E2F family members in large part using the recently described SAGE (Serial Analysis of Gene Expression) technology. 2) an investigation of the mechanism underlying transcriptional specificity including a determination of the relative contributions of different protein domains to target specificity. 3) characterization of the specific role of E2F1 as a mediator of apoptosis during the selection of the T cell repertoire, in part by utilizing T cell receptor transgenic mice. 4) a molecular analysis of how E2F activities are both controlled by and contribute to pathways which lead to apoptosis in lymphocytes by employing a thymocyte in vitro negative selection assay. These studies will further our understanding of the individual contributions of the different E2F family members towards the control of cell growth and apoptosis, and should help elucidate the pathways which regulate apoptosis in lymphocytes, the deregulation of which contributes to both autoimmune disease and cancer.
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