Accelerated Notch-dependent degradation of E47 proteins in aged B cell precursors is associated with increased ERK MAPK activation.
The transcriptional regulator E47, encoded by the E2A gene, is crucial to B lymphopoiesis. In BALB/c senescent mice (approximately 2 years old), the incidence of E47-expressing pro-B cells in vivo and E47 protein steady state levels in B cell precursors in vitro were reduced. Poor expression of E47 protein was a consequence of accelerated proteasome-mediated turnover and was associated with heightened ubiquitin modification of E2A-encoded proteins in aged B cell precursors. Both MAPK and Notch activity have been previously associated with E2A-encoded protein stability in lymphocytes. Aged B cell precursors exhibited heightened levels of MAPK activity reflected in increased levels of phospho-ERK proteins. Phosphorylation of E2A-encoded proteins was also increased in aged B cell precursors and pharmacologic inhibition of MEK-1 resulted in a partial restoration of their E47 protein. Both Notch proteins and their Delta-like ligands were detected comparably in young and aged B cell precursors. Either inhibition of Notch activation via gamma-secretase or Ab blockade of Notch-Delta-like ligand interactions partially restored E47 expression in aged B cell precursors. We hypothesize that increased MAPK activity promotes phosphorylation of E2A-encoded protein in aged B cell precursors. Subsequently, E2A-encoded proteins undergo ubiquitination and accelerated degradation in a Notch-dependent process. The dysregulation of E2A-encoded protein expression may contribute to the reductions seen in early B lymphopoiesis during murine senescence.
King
Anne M
AM
Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33101, USA.
Van der Put
Elaine
E
Blomberg
Bonnie B
BB
Riley
Richard L
RL
D000375:Aging / Q000276:immunology / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000276:immunology / Q000378:metabolism; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D051792:Basic Helix-Loop-Helix Proteins / Q000276:immunology / Q000378:metabolism*; D004789:Enzyme Activation / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000276:immunology; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000378:metabolism*; D038041:Lymphopoiesis / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000276:immunology / Q000378:metabolism; D011498:Protein Precursors / Q000276:immunology / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000276:immunology; D051880:Receptors, Notch / Q000276:immunology / Q000378:metabolism*; D025801:Ubiquitin / Q000276:immunology / Q000378:metabolism
D053829:Amyloid Precursor Protein Secretases; D051792:Basic Helix-Loop-Helix Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D046988:Proteasome Endopeptidase Complex; D011498:Protein Precursors; D051880:Receptors, Notch; D025801:Ubiquitin; C075668:Tcf3 protein, mouse