Constitutive activation of NF-κB and T-cell leukemia/lymphoma in Notch3 transgenic mice
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 Notc...
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Published in | The EMBO journal Vol. 19; no. 13; pp. 3337 - 3348 |
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Main Authors | , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Chichester, UK
John Wiley & Sons, Ltd
03.07.2000
Oxford University Press |
Subjects | |
Online Access | Get full text |
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Summary: | 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‐κB. Subsequently, aggressive multicentric T‐cell lymphomas developed with high penetrance. Tumors sustained characteristics of immature thymocytes, including expression of CD25, pTα and activated NF‐κB via IKKα‐dependent degradation of IκBα and enhancement of NF‐κB‐dependent anti‐apoptotic and proliferative pathways. Together, these data identify activated Notch3 as a link between signals leading to NF‐κB 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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Bibliography: | istex:488AE3BE63C67AFB809698119D1CCDA2C4BBB5CC ArticleID:EMBJ7593153 ark:/67375/WNG-18C5DH79-1 ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 D.Bellavia and A.F.Campese contributed equally to this work Corresponding author e-mail: screpant@caspur.it |
ISSN: | 0261-4189 1460-2075 |
DOI: | 10.1093/emboj/19.13.3337 |