Inhibition of EBF function by active Notch signaling reveals a novel regulatory pathway in early B-cell development.
The Notch signaling pathway is involved in several lineage commitment and differentiation events. One of these is fate determination of the common lymphoid progenitor, promoting T-cell development at the expense of B-cell differentiation. It has been suggested that this process relies on Notch's ability to inhibit E proteins, which are crucial for early B-cell development. Here, we report that Notch signaling also modulates the function of the transcription factor, early B-cell factor (EBF). Transient transfection of intracellular Notch1 (Notch1-IC) into a pre-B cell line resulted in the down-regulation of EBF-regulated promoters and diminished the capacity of EBF to activate these promoters in an epithelial cell line. This correlated with a reduction in the ability of EBF to bind DNA. Ligand-induced stimulation of endogenous Notch receptors with Delta4 mimicked the activity of Notch1-IC toward EBF. These data suggest that Notch signaling may affect B-versus T-lineage commitment by the targeting of both EBF and E2A.
Smith
Emma M K
EM
Department for Stem Cell Biology, Lund University, BMC B12, S-221 84 Lund, Sweden.
Akerblad
Peter
P
Kadesch
Tom
T
Axelson
Håkan
H
Sigvardsson
Mikael
M
D048868:Adaptor Proteins, Signal Transducing; D001402:B-Lymphocytes / Q000166:cytology*; D051792:Basic Helix-Loop-Helix Proteins; D001798:Blood Proteins; D002135:Calcium-Binding Proteins; D002460:Cell Line; D019070:Cell Lineage; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D015536:Down-Regulation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000502:physiology*; D011401:Promoter Regions, Genetic; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface / Q000502:physiology; D051880:Receptors, Notch; D015398:Signal Transduction; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D051792:Basic Helix-Loop-Helix Proteins; D001798:Blood Proteins; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D015534:Trans-Activators; D014157:Transcription Factors; C424126:DLL4 protein, human; C081976:EBF1 protein, human; C497761:NOTCH1 protein, human; C407909:TCF3 protein, human