Regulation of the Lymphocytic cell cycle by E2F
Biography Overview E2F activity is critical for the control of the G1 to S phase transition, and the pathway leading to E2F activation is deregulated in most human tumors. The combined loss of E2F1 and E2F2 results in profound effects on hematopoietic cell proliferation, pancreatic maintenance, tumor suppression, and lymphocyte tolerance. Roles for E2F1 and E2F2 in limiting T-cell proliferation are in contrast to clear roles in facilitating S phase progression, as hematopoietic progenitor cells in E2F1/2 mutant mice demonstrate remarkably delayed S phase progression, contributing to highly inefficient hematopoiesis. Finally, E2F1 and E2F2 appear to be specifically required for the regulation of specific target genes, such as Cyclin A2, which may underlie roles for E2F1/2 in S phase progression. The mechanism underlying E2F1/2 dependent transcriptional specificity will be explored. We propose experiments to characterize E2F1/2 dependent target genes and link the E2F 1/2 dependent regulation of target genes with roles for E2F 1/2 in cell cycle progression, with the eventual goal of connecting these transcriptional and cellular roles with organismal phenotypes observed in E2F1/2 KO mice. We propose three specific aims: 1) Identification and characterization of E2F1 and E2F2 target genes that negatively regulate lymphocyte proliferation. 2) Interrogation of identified target genes as potential mediators of E2F 1/2 dependent control of T-cell proliferation in response to antigen. 3) Exploration of the mechanisms that underlie roles for E2F2 in facilitating S phase progression and hematopoiesis. These studies will combine the powers of gene targeted mice, genome wide analysis of gene expression, inhibition of gene expression by RNAi, and technology developed in our lab that facilitates gene transfer to primary T-cells. Understanding the cellular functions of E2F1/2 and their target genes should facilitate a better understanding of organismal roles for these E2Fs at a more mechanistic level.
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