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 journalArticle

94 Citations (Scopus)

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

Fingerprint

T-Cell Leukemia
T-cells
Thymocytes
Interleukin-7 Receptors
Genes
Chemical activation
Cell Differentiation
Dimerization
Cyclin D1
Transcription
T-Cell Lymphoma
Multigene Family
Transgenic Mice
Molecular Biology
Cell Proliferation
Processing
T-Lymphocytes

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

Vacca, A., Felli, M. P., Palermo, R., Di Mario, G., Calce, A., Di Giovine, M., ... Screpanti, I. (2006). Notch3 and pre-TCR interaction unveils distinct NF-κB pathways in T-cell development and leukemia. EMBO Journal, 25(5), 1000-1008. https://doi.org/10.1038/sj.emboj.7600996

Notch3 and pre-TCR interaction unveils distinct NF-κB pathways in T-cell development and leukemia. / Vacca, Alessandra; Felli, Maria Pia; Palermo, Rocco; Di Mario, Giuseppina; Calce, Angelica; Di Giovine, Monica; Frati, Luigi; Gulino, Alberto; Screpanti, Isabella.

In: EMBO Journal, Vol. 25, No. 5, 08.03.2006, p. 1000-1008.

Research output: Contribution to journalArticle

Vacca, A, Felli, MP, Palermo, R, Di Mario, G, Calce, A, Di Giovine, M, Frati, L, Gulino, A & Screpanti, I 2006, 'Notch3 and pre-TCR interaction unveils distinct NF-κB pathways in T-cell development and leukemia', EMBO Journal, vol. 25, no. 5, pp. 1000-1008. https://doi.org/10.1038/sj.emboj.7600996
Vacca A, Felli MP, Palermo R, Di Mario G, Calce A, Di Giovine M et al. Notch3 and pre-TCR interaction unveils distinct NF-κB pathways in T-cell development and leukemia. EMBO Journal. 2006 Mar 8;25(5):1000-1008. https://doi.org/10.1038/sj.emboj.7600996
Vacca, Alessandra ; Felli, Maria Pia ; Palermo, Rocco ; Di Mario, Giuseppina ; Calce, Angelica ; Di Giovine, Monica ; Frati, Luigi ; Gulino, Alberto ; Screpanti, Isabella. / Notch3 and pre-TCR interaction unveils distinct NF-κB pathways in T-cell development and leukemia. In: EMBO Journal. 2006 ; Vol. 25, No. 5. pp. 1000-1008.
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