The overall objective of the research proposed in this grant application is to examine the regulation and function of E-proteins in T cell development and lymphomagenesis. E2A and HEB are helix-loop-helix proteins that play important roles throughout T-lineage maturation. Additionally, E2A and HEB function as tumor suppressors. In developing T cells the E2A proteins activate RAG2 gene expression, induce TCR beta gene rearrangement and regulate cell cycle progression. During the pre-TCR and alpha/beta TCR checkpoints, E2A/HEB DNA binding activity is controlled by the ras-Erk MAP kinase pathway. The regulation of E2A DNA binding activity is mediated, at least in part, through the induction of Id3 gene expression and by modulation of E2A protein synthesis. Here we propose to continue these studies. We would investigate the individual roles of E12, E47 and HEB in T-lineage development, lymphomagenesis and cell cycle progression. We would identify E12 and E47 target genes required to promote developmental maturation and cellular proliferation. We would examine mechanistically how E2A proteins regulate cell cycle progression both in vitro and in vivo. We would further define the pathway leading to the activation of Id3 expression. We would examine whether ras mediated transformation requires Id3 gene expression. Furthermore, we would examine how E2A protein synthesis is modulated during T-lineage development. Overall the dissection of the roles of E-proteins and Id3 in T-lineage development should help to clarify the mechanism of how HLH proteins regulate T cell homeostasis and lymphomagenesis. ? ?
