UC San Diego

The helix-loop-helix (HLH) transcription factors constitute a highly conserved family of proteins that are involved in the regulation of a variety of developmental pathways. The PI3K-AKT signaling cascade acts to modulate the activity of multiple effectors to regulate developmental progression and cell growth. We demonstrate that the HLH protein, E47, was phosphorylated at a serine residue, in a region containing a highly conserved AKT substrate site. The observations described in this thesis show that in naïve B cells, high PIP3 levels generated by tonic BCR/CD19 mediated signaling, promote the rapid degradation of E47, while in activated B cells, PTEN functions to allow E47 abundance to accumulate and activate AID expression and CSR. Furthermore, we show that PTEN during early T-lineage development functions to prevent degradation of E47 by PI3K-mediated signaling, enforcing the pre-TCR checkpoint. Our data also demonstrate that E47 activity substantially decreases cell size in PTEN-deficient lymphomas. Finally, we demonstrate that E47 activity is regulated by PTEN to prevent the development of lymphoma. Collectively, our studies demonstrate that that E47 acts as a nodal point in the PI3K/AKT signaling pathway and that in T cells, the tumor suppressor activity of PTEN to regulate cellular expansion is directly connected to E47