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- Title
Constitutive activation of NF-kappaB and T-cell leukemia/lymphoma in Notch3 transgenic mice.
- Authors
Bellavia, D; Campese, A F; Alesse, E; Vacca, A; Felli, M P; Balestri, A; Stoppacciaro, A; Tiveron, C; Tatangelo, L; Giovarelli, M; Gaetano, C; Ruco, L; Hoffman, E S; Hayday, A C; Lendahl, U; Frati, L; Gulino, A; Screpanti, I
- Abstract
The multiplicity of Notch receptors raises the question of the contribution of specific isoforms to T-cell development. Notch3 is expressed in CD4(-)8(-) thymocytes and is down-regulated across the CD4(-)8(-) to CD4(+)8(+) transition, controlled by pre-T-cell receptor signaling. To determine the effects of Notch3 on thymocyte development, transgenic mice were generated, expressing lck promoter-driven intracellular Notch3. Thymuses of young transgenics showed an increased number of thymocytes, particularly late CD4(-)8(-) cells, a failure to down-regulate CD25 in post-CD4(-)8(-) subsets and sustained activity of NF-kappaB. Subsequently, aggressive multicentric T-cell lymphomas developed with high penetrance. Tumors sustained characteristics of immature thymocytes, including expression of CD25, pTalpha and activated NF-kappaB via IKKalpha-dependent degradation of IkappaBalpha and enhancement of NF-kappaB-dependent anti-apoptotic and proliferative pathways. Together, these data identify activated Notch3 as a link between signals leading to NF-kappaB activation and T-cell tumorigenesis. The phenotypes of pre-malignant thymocytes and of lymphomas indicate a novel and particular role for Notch3 in co-ordinating growth and differentiation of thymocytes, across the pre-T/T cell transition, consistent with the normal expression pattern of Notch3.
- Publication
The EMBO journal, 2000, Vol 19, Issue 13, p3337
- ISSN
0261-4189
- Publication type
Journal Article
- DOI
10.1093/emboj/19.13.3337