The long term goal of this work is to understand the transcriptional mechanisms that underlie B lymphocyte identity. In a broad sense, the work also intends, by contrast, to further our understanding of transcriptional regulation in other cell types, including T lymphocytes and myeloid cells, and to serve as a point of departure for investigating the molecular basis of hematopoietic malignancies. The work proposed here intends to characterize the E2A protein and, specifically, to identify the cause of its activation in B cells. Initially identified as an immunoglobulin enhancer-binding protein, E2A has since been implicated not only in B cell development, but in helping to establish cell type-restricted transcription in several other cell types. In particular, E2A has been shown to be an active collaborator of MyoD and myogenin, two proteins that initiate cascades of muscle-specific transcription. E2A's activity is regulated: protein is present in virtually all cells, but its ability to bind DNA is cell-restricted. B cells contain a form of E2A that is active, and that appears to be unique. Its activation early in the B lineage suggests an important role in influencing B lymphocyte identity.
The specific aims of the proposed work are to: l) investigate the intrinsic nature of E2A proteins from B cells as compared to E2A from other cell types; 2) characterize E2A-interacting proteins in B cells and non-B cells; and 3) examine the role of post-translational modifications (e.g., phosphorylation) in regulating E2A DNA-binding activity.
These aims are designed to address the fundamental differences between B cells and non-B cells as they pertain to the activation of this pivotal protein.
| Zhao, Fang; McCarrick-Walmsley, Ruth; Akerblad, Peter et al. (2003) Inhibition of p300/CBP by early B-cell factor. Mol Cell Biol 23:3837-46 |
