Notch-1 regulates NF-kappaB activity in hemopoietic progenitor cells.
We investigated the interaction between two elements critical for differentiation of hemopoietic cells, the Notch-1 receptor and the transcription factor NF-kappaB. These factors were studied in hemopoietic progenitor cells (HPC) using Notch-1 antisense transgenic (Notch-AS-Tg) mice. DNA binding of NF-kappaB as well as its ability to activate transcription was strongly decreased in HPC from Notch-AS-Tg mice. NF-kappaB-driven transcriptional activity was completely restored after transduction of the cells with retroviral constructs containing activated Notch-1 gene. HPC from Notch-AS-Tg mice have decreased levels of several members of the NF-kappaB family, p65, p50, RelB, and c-Rel and this is due to down-regulation of the gene expression. To investigate functional consequences of decreased NF-kappaB activity in transgenic mice, we studied LPS-induced proliferation of B cells and GM-CSF-dependent differentiation of dendritic cells from HPC. These two processes are known to be closely dependent on NF-kappaB. B cells from Notch-AS-Tg mice had almost 3-fold lower response to LPS than B cells isolated from control mice. Differentiation of dendritic cells was significantly affected in Notch-AS-Tg mice. However, it was restored by transduction of activated Notch-1 into HPC. Taken together, these data indicate that in HPC NF-kappaB activity is regulated by Notch-1 via transcriptional control of NF-kappaB.
Cheng
P
P
H. Lee Moffitt Cancer Center, University of South Florida, Tampa, FL 33612, USA.
Zlobin
A
A
Volgina
V
V
Gottipati
S
S
Osborne
B
B
Simel
E J
EJ
Miele
L
L
Gabrilovich
D I
DI
D000818:Animals; D016375:Antisense Elements (Genetics); D001402:B-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000166:cytology; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics*; D021122:Protein Subunits; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D014158:Transcription, Genetic
D016375:Antisense Elements (Genetics); D008070:Lipopolysaccharides; D008565:Membrane Proteins; D016328:NF-kappa B; C497762:Notch1 protein, mouse; D021122:Protein Subunits; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D014157:Transcription Factors