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 pTalpha/pre-TCR and display constitutive activation of NF-kB, providing survival signals for immature thymocytes. We provide genetic and biochemical evidence that Notch3 triggers multiple NF-kB activation pathways. A pre-TCR-dependent pathway preferentially activates NF-kB via IKKbeta/IKKalpha/NIK complex, resulting in p50/p65 heterodimer nuclear entry and recruitment onto promoters of Cyclin D1, Bcl2-A1 and IL7-receptor-alpha genes. In contrast, upon pTalpha deletion, Notch3 binds IKKalpha and maintains NF-kB activation through an alternative pathway, depending on an NIK-independent IKKalpha homodimer activity. The consequent NF-kB2/p100 processing allows nuclear translocation of p52/RelB heterodimers, which only trigger transcription from Bcl2-A1 and IL7-receptor-alpha genes. Our data suggest that a finely tuned interplay between Notch3 and pre-TCR pathways converges on regulation of NF-kB activity, leading to differential NF-kB subunit dimerization that regulates distinct gene clusters involved in either cell differentiation or proliferation/ leukemogenesis.

Notch3 and pre-TCR interaction unveils distinct NF-kappaB pathways in T-cell development and leukemia / Vacca, Alessandra; Felli, MARIA PIA; Palermo, Rocco; DI MARIO, G; Calce, A; DI GIOVINE, Monica; Frati, Luigi; Gulino, Alberto; Screpanti, Isabella. - In: EMBO JOURNAL. - ISSN 0261-4189. - STAMPA. - 25(5):(2006), pp. 1000-1008. [10.1038/sj.emboj.7600996]

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

VACCA, Alessandra;FELLI, MARIA PIA;PALERMO, ROCCO;DI GIOVINE, Monica;FRATI, Luigi;GULINO, Alberto;SCREPANTI, Isabella
2006

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 pTalpha/pre-TCR and display constitutive activation of NF-kB, providing survival signals for immature thymocytes. We provide genetic and biochemical evidence that Notch3 triggers multiple NF-kB activation pathways. A pre-TCR-dependent pathway preferentially activates NF-kB via IKKbeta/IKKalpha/NIK complex, resulting in p50/p65 heterodimer nuclear entry and recruitment onto promoters of Cyclin D1, Bcl2-A1 and IL7-receptor-alpha genes. In contrast, upon pTalpha deletion, Notch3 binds IKKalpha and maintains NF-kB activation through an alternative pathway, depending on an NIK-independent IKKalpha homodimer activity. The consequent NF-kB2/p100 processing allows nuclear translocation of p52/RelB heterodimers, which only trigger transcription from Bcl2-A1 and IL7-receptor-alpha genes. Our data suggest that a finely tuned interplay between Notch3 and pre-TCR pathways converges on regulation of NF-kB activity, leading to differential NF-kB subunit dimerization that regulates distinct gene clusters involved in either cell differentiation or proliferation/ leukemogenesis.
2006
01 Pubblicazione su rivista::01a Articolo in rivista
Notch3 and pre-TCR interaction unveils distinct NF-kappaB pathways in T-cell development and leukemia / Vacca, Alessandra; Felli, MARIA PIA; Palermo, Rocco; DI MARIO, G; Calce, A; DI GIOVINE, Monica; Frati, Luigi; Gulino, Alberto; Screpanti, Isabella. - In: EMBO JOURNAL. - ISSN 0261-4189. - STAMPA. - 25(5):(2006), pp. 1000-1008. [10.1038/sj.emboj.7600996]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/362204
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