Abstract
Notch signaling plays a critical role in T-cell differentiation and leukemogenesis. We previously demonstrated that, while pre-TCR is required for thymocytes proliferation and leukemogenesis, it is dispensable for thymocyte differentiation in Notch3-transgenic mice. Notch3-transgenic premalignant thymocytes and T lymphoma cells over-express pTα/pre-TCR and display constitutive activation of NF-κB, providing survival signals for immature thymocytes. We provide genetic and biochemical evidence that Notch3 triggers multiple NF-κB activation pathways. A pre-TCR-dependent pathway preferentially activates NF-κB via IKKβ/IKKα/NIK complex, resulting in p50/p65 heterodimer nuclear entry and recruitment onto promoters of Cyclin D1, Bcl2-A1 and IL7-receptor-α genes. In contrast, upon pTα deletion, Notch3 binds IKKα and maintains NF-κB activation through an alternative pathway, depending on an NIK-independent IKKα homodimer activity. The consequent NF-κB2/p100 processing allows nuclear translocation of p52/RelB heterodimers, which only trigger transcription from Bcl2-A1 and IL7-receptor-α genes. Our data suggest that a finely tuned interplay between Notch3 and pre-TCR pathways converges on regulation of NF-κB activity, leading to differential NF-κB subunit dimerization that regulates distinct gene clusters involved in either cell differentiation or proliferation/leukemogenesis.
Original language | English |
---|---|
Pages (from-to) | 1000-1008 |
Number of pages | 9 |
Journal | EMBO Journal |
Volume | 25 |
Issue number | 5 |
DOIs | |
Publication status | Published - Mar 8 2006 |
Keywords
- IKKα
- NF-κB pathways
- Notch3
- Pre-TCR
ASJC Scopus subject areas
- Genetics
- Cell Biology