PUBLICATION
The nuclear pore proteins Nup88/214 and T-ALL-associated NUP214 fusion proteins regulate Notch signaling
- Authors
- Kindermann, B., Valkova, C., Krämer, A., Perner, B., Engelmann, C., Behrendt, L., Kritsch, D., Jungnickel, B., Kehlenbach, R.H., Oswald, F., Englert, C., Kaether, C.
- ID
- ZDB-PUB-190613-3
- Date
- 2019
- Source
- The Journal of biological chemistry 294(31): 11741-11750 (Journal)
- Registered Authors
- Englert, Christoph, Perner, Birgit
- Keywords
- Notch pathway, T-cell acute lymphatic leukemia (T-ALL), cancer, cell compartmentalization, cell signaling, gene regulation, leukemia, nuclear pore, nuclear transport, nucleoporin 214 (Nup214), nucleoporin 88 (Nup88), recombination signal–binding protein for immunoglobulin kappa J region (RBP-J)
- MeSH Terms
-
- Active Transport, Cell Nucleus
- Animals
- Cell Line, Tumor
- Humans
- Immunoglobulin J Recombination Signal Sequence-Binding Protein/metabolism
- Morpholinos/genetics
- Morpholinos/metabolism
- Nuclear Pore Complex Proteins/antagonists & inhibitors
- Nuclear Pore Complex Proteins/genetics
- Nuclear Pore Complex Proteins/metabolism*
- Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism
- Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology*
- RNA Interference
- RNA, Small Interfering/metabolism
- Receptors, Notch/metabolism
- Recombinant Fusion Proteins/genetics
- Recombinant Fusion Proteins/metabolism
- Signal Transduction*
- Transcription Factor HES-1/antagonists & inhibitors
- Transcription Factor HES-1/genetics
- Transcription Factor HES-1/metabolism
- Zebrafish/metabolism
- Zebrafish Proteins/antagonists & inhibitors
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 31186352 Full text @ J. Biol. Chem.
Citation
Kindermann, B., Valkova, C., Krämer, A., Perner, B., Engelmann, C., Behrendt, L., Kritsch, D., Jungnickel, B., Kehlenbach, R.H., Oswald, F., Englert, C., Kaether, C. (2019) The nuclear pore proteins Nup88/214 and T-ALL-associated NUP214 fusion proteins regulate Notch signaling. The Journal of biological chemistry. 294(31):11741-11750.
Abstract
The Notch receptor is a key mediator of developmental programs and cell-fate decisions. Imbalanced Notch signaling leads to developmental disorders and cancer. To fully characterize the Notch signaling pathway and exploit it in novel therapeutic interventions, a comprehensive view on the regulation and requirements of Notch signaling is needed. Notch is regulated at different levels, ranging from ligand binding, stability to endocytosis. Using an array of different techniques, including reporter gene assays, immunocytochemistry and ChIP-qPCR we show here, to the best of our knowledge for the first time, regulation of Notch signaling at the level of the nuclear pore. We found that the nuclear pore protein nucleoporin 214 (Nup214) and its interaction partner Nup88 negatively regulate Notch signaling in vitro and in vivo in zebrafish. In mammalian cells, loss of Nup88/214 inhibited nuclear export of recombination signal-binding protein for immunoglobulin kappa J region (RBP-J), the DNA-binding component of the Notch pathway. This increased binding of RBP-J to its cognate promoter regions, resulting in increased down-stream Notch signaling. Interestingly, we also found that NUP214 fusion proteins, causative for certain cases of T-cell Acute Lymphatic Leukemia, potentially contribute to tumorigenesis via a Notch-dependent mechanism. In summary, the nuclear pore components Nup88/214 suppress Notch signaling in vitro and in zebrafish, nuclear RBP-J levels are rate-limiting factors for Notch signaling in mammalian cells, and regulation of nucleocytoplasmic transport of RBP-J may contribute to fine-tuning Notch activity in cells.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping