期刊
EMBO JOURNAL
卷 25, 期 5, 页码 1000-1008出版社
WILEY
DOI: 10.1038/sj.emboj.7600996
关键词
IKK alpha; NF-kappa B pathways; notch3; pre-TCR
Notch signaling plays a critical role in T-cell differentiation and leukemogenesis. We previously demonstrated that, while pre-TCR is required for thymocytes proliferation and leukemogenesis, it is dispensable for thymocyte differentiation in Notch3-transgenic mice. Notch3-transgenic premalignant thymocytes and T lymphoma cells overexpress pT alpha/pre-TCR and display constitutive activation of NF-kappa B, providing survival signals for immature thymocytes. We provide genetic and biochemical evidence that Notch3 triggers multiple NF-kappa B activation pathways. A pre-TCR-dependent pathway preferentially activates NF-kappa B via IKK beta/IKK alpha/NIK complex, resulting in p50/p65 heterodimer nuclear entry and recruitment onto promoters of Cyclin D1, Bcl2-A1 and IL7-receptor-alpha genes. In contrast, upon pT alpha deletion, Notch3 binds IKK alpha and maintains NF-kappa B activation through an alternative pathway, depending on an NIK-independent IKKa homodimer activity. The consequent NF-kappa B2/p100 processing allows nuclear translocation of p52/RelB heterodimers, which only trigger transcription from Bcl2-A1 and IL7-receptor-alpha genes. Our data suggest that a finely tuned interplay between Notch3 and pre-TCR pathways converges on regulation of NF-kappa B activity, leading to differential NF-kappa B subunit dimerization that regulates distinct gene clusters involved in either cell differentiation or proliferation/leukemogenesis.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据