Title

Reduced B Lymphopoiesis In Senescence Is Associated With Altered Regulation Of E2a-Encoded Proteins

Date of Award

2007

Availability

Article

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Microbiology and Immunology

First Committee Member

Richard L. Riley, Committee Chair

Abstract

The transcriptional regulator E47, encoded by the E2A gene, is crucial to B lymphopoiesis and is reduced in B cell precursors from senescent mice (∼2 yrs. old). Poor expression of E47 protein is a consequence of accelerated proteasome-mediated turnover and is associated with heightened ubiquitin modification of E2A-encoded proteins in aged B cell precursors. Both MAPK and Notch activity have been associated with E2A-encoded protein stability. We have determined that aged B cell precursors exhibit heightened activity of the Ras-MEK-Erk MAPK pathway as evidenced by increased levels of phospho-ERK proteins (p42/p44) and pharmacologic inhibition of MEK-1 resulted in a partial restoration of E47 protein in aged B cell precursors. Both Notch proteins and their Delta-like ligands (DLL) were detected in young and aged B cell precursors. Inhibition of Notch activation via gamma-secretase or antibody blockade of Notch-Delta-like ligand interactions partially restored E47 expression in aged B cell precursors. These studies suggest that alterations in the MAPK and/or Notch activation pathways may promote E47 protein turnover and contribute to loss of B cell precursors in senescence.We have also begun to assess the role of the bone marrow microenvironment in regulating E47 protein expression in both young and aged mice. We identified a population of bone marrow cells characterized as CD19- B220+ that reduced E47 protein in B cell precursors. This was independent of cell contact and included cells with a DX5+ CD11c+ phenotype characteristic of NK-like cells. While these inhibitory cells appear to function comparably in young and aged mice, their numbers are increased in some aged mice. These results suggest that E47 protein levels in B cell precursors are susceptible to regulation by cells within the bone marrow microenvironment. In senescent mice, these (and potentially other) regulatory cells may participate in limiting E2A protein expression and, consequently, B lymphopoiesis.

Keywords

Health Sciences, Immunology

Link to Full Text

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