Journal
EMBO JOURNAL
Volume 19, Issue 13, Pages 3337-3348Publisher
OXFORD UNIV PRESS
DOI: 10.1093/emboj/19.13.3337
Keywords
NF-kappa B; Notch3; pre-TCR; T-cell malignancy
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Funding
- Telethon [B.40] Funding Source: Medline
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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-kappa B, Subsequently, aggressive multicentric T-cell lymphomas developed with high penetrance, Tumors sustained characteristics of immature thymocytes, including expression of CD25, pT alpha and activated NF-kappa B via IKR alpha-dependent degradation of I kappa B alpha and enhancement of NF-kappa B-dependent anti-apoptotic and proliferative pathways. Together, these data identify activated Notch3 as a link between signals leading to NF-kappa B 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.
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