Notch3 and pre-TCR interaction unveils distinct NF-κB pathways in T-cell development and leukemia

Alessandra Vacca, Maria Pia Felli, Rocco Palermo, Giuseppina Di Mario, Angelica Calce, Monica Di Giovine, Luigi Frati, Alberto Gulino, Isabella Screpanti

Research output: Contribution to journalArticlepeer-review

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 languageEnglish
Pages (from-to)1000-1008
Number of pages9
JournalEMBO Journal
Volume25
Issue number5
DOIs
Publication statusPublished - Mar 8 2006

Keywords

  • IKKα
  • NF-κB pathways
  • Notch3
  • Pre-TCR

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

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