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IkappaBalpha and p65 regulate the cytoplasmic shuttling of nuclear corepressors: cross-talk between Notch and NFkappaB pathways.
- Source :
-
Molecular biology of the cell [Mol Biol Cell] 2003 Feb; Vol. 14 (2), pp. 491-502. - Publication Year :
- 2003
-
Abstract
- Notch and NFkappaB 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-NFkappaB mutant that lacks the transactivation domain (p65DeltaTA) induces cytoplasmic translocation of N-CoR leading to a positive regulation of different promoters. Now, we show that cytoplasmic sequestration of p65 by IkappaBalpha is sufficient to both translocate nuclear corepressors SMRT/N-CoR to the cytoplasm and upregulate transcription of Notch-dependent genes. Moreover, p65 and IkappaBalpha 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-alpha treatment, suggesting that p65 acetylation is modulating this interaction. In agreement with this, TNF-alpha 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.
- Subjects :
- 3T3 Cells
Active Transport, Cell Nucleus
Animals
Apoptosis
Binding, Competitive
Blotting, Northern
Blotting, Western
Cell Differentiation
Cell Division
Cell Line
Dose-Response Relationship, Drug
Down-Regulation
Flow Cytometry
Humans
I-kappa B Proteins metabolism
Luciferases metabolism
Mice
Microscopy, Fluorescence
NF-KappaB Inhibitor alpha
Plasmids metabolism
Precipitin Tests
Protein Binding
Protein Structure, Tertiary
Receptors, Notch
Synaptotagmin I
Synaptotagmins
Transcriptional Activation
Tumor Necrosis Factor-alpha metabolism
Up-Regulation
Calcium-Binding Proteins
Cell Nucleus metabolism
Cytoplasm metabolism
I-kappa B Proteins physiology
Membrane Glycoproteins physiology
Membrane Proteins metabolism
NF-kappa B metabolism
Nerve Tissue Proteins physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1059-1524
- Volume :
- 14
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Molecular biology of the cell
- Publication Type :
- Academic Journal
- Accession number :
- 12589049
- Full Text :
- https://doi.org/10.1091/mbc.e02-07-0404