Constitutive activation of NF-kappaB 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 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.
Bellavia
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Department of Experimental Medicine and Pathology, University La Sapienza, Roma, Italy.
Campese
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Alesse
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Vacca
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Felli
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Balestri
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Stoppacciaro
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Tiveron
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Tatangelo
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Giovarelli
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Gaetano
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Ruco
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Hoffman
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Hayday
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Lendahl
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Frati
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Gulino
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Screpanti
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D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D002470:Cell Survival; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000502:physiology; D020672:I-kappa B Proteins; D015458:Leukemia, T-Cell / Q000378:metabolism* / Q000473:pathology; D016399:Lymphoma, T-Cell / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D000071656:Receptor, Notch3; D000074562:Receptor, Notch4; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D051880:Receptors, Notch; D013950:Thymus Gland / Q000473:pathology
D017931:DNA Primers; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; C499373:Notch3 protein, mouse; D011518:Proto-Oncogene Proteins; D000071656:Receptor, Notch3; D000074562:Receptor, Notch4; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D000072000:NF-KappaB Inhibitor alpha; C073572:Notch4 protein, mouse