We investigated the interaction between two elements critical for different
iation of hemopoietic cells, the Notch-1 receptor and the transcription fac
tor NF-KB. These factors were studied in hemopoietic progenitor cells (HPC)
using Notch-1 antisense transgenic (Notch-AS-Tg) mice. DNA binding of NF-k
appaB as well as its ability to activate transcription was strongly decreas
ed in HPC from Notch-AS-Tg mice. NF-KB-driven transcriptional activity was
completely restored after transduction of the cells with retroviral constru
cts containing activated Notch-1 gene. HPC from Notch-AS-Tg mice have decre
ased 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 invest
igate 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 al
most 3-fold lower response to LPS than B cells isolated from control mice.
Differentiation of dendritic cells was significantly affected in Notch-AS-T
g 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-KB.