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
Department of Experimental Medicine and Pathology, University La Sapienza, Roma, Italy.
EMBO J. 2000 Jul 3;19(13):3337-48. doi: 10.1093/emboj/19.13.3337.
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.
Notch受体的多样性引发了特定异构体对T细胞发育贡献的问题。Notch3在CD4(-)8(-)胸腺细胞中表达，并在从CD4(-)8(-)到CD4(+)8(+)的转变过程中受前T细胞受体信号控制而下调。为了确定Notch3对胸腺细胞发育的影响，构建了表达lck启动子驱动的细胞内Notch3的转基因小鼠。年轻转基因小鼠的胸腺显示胸腺细胞数量增加，特别是晚期CD4(-)8(-)细胞，CD4(-)8(-)后亚群中CD25未能下调以及NF-κB持续激活。随后，侵袭性多中心T细胞淋巴瘤高频率发生。肿瘤保持未成熟胸腺细胞的特征，包括CD25、pTα的表达以及通过IKKα依赖的IkappaBα降解和NF-κB依赖的抗凋亡和增殖途径增强而激活的NF-κB。总之，这些数据确定激活的Notch3是导致NF-κB激活的信号与T细胞肿瘤发生之间的联系。癌前胸腺细胞和淋巴瘤的表型表明Notch3在协调胸腺细胞跨越前T/T细胞转变的生长和分化中具有新的特殊作用，这与Notch3的正常表达模式一致。
