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Vol. 14, Issue 2, 491-502, February 2003
B
and p65 Regulate the Cytoplasmic Shuttling of Nuclear
Corepressors: Cross-talk between Notch and NFB Pathways
Centre Oncologia Molecular, Institut de Recerca
Oncologica, Hospitalet, Barcelona 08907, Spain
Notch and NF
B pathways are key regulators of numerous cellular
events such as proliferation, differentiation, or apoptosis. In both
pathways, association of effector proteins with nuclear corepressors is
responsible for their negative regulation. We have previously described
that expression of a p65-NFB mutant that lacks the transactivation
domain (p65
TA) induces cytoplasmic translocation of N-CoR leading to
a positive regulation of different promoters. Now, we show that
cytoplasmic sequestration of p65 by IB
is sufficient to both
translocate nuclear corepressors SMRT/N-CoR to the cytoplasm and
upregulate transcription of Notch-dependent genes. Moreover, p65 and
IB are able to directly bind SMRT, and this interaction can be
inhibited in a dose-dependent manner by the CREB binding protein (CBP)
coactivator and after TNF- treatment, suggesting that p65
acetylation is modulating this interaction. In agreement with this,
TNF- treatment results in downregulation of the Hes1 gene. Finally,
we present evidence on how this mechanism may influence cell
differentiation in the 32D myeloid progenitor system.
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