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- Title
Notch3 and pre-TCR interaction unveils distinct NF-κB pathways in T-cell development and leukemia.
- Authors
Vacca, Alessandra; Felli, Maria Pia; Palermo, Rocco; Di Mario, Giuseppina; Calce, Angelica; Di Giovine, Monica; Frati, Luigi; Gulino, Alberto; Screpanti, Isabella
- 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 overexpress 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.
- Subjects
CELLULAR signal transduction; PHYSIOLOGICAL control systems; NF-kappa B; DNA-binding proteins; TRANSCRIPTION factors; LEUKEMIA
- Publication
EMBO Journal, 2006, Vol 25, Issue 5, p1000
- ISSN
0261-4189
- Publication type
Article
- DOI
10.1038/sj.emboj.7600996