Notch1 antiapoptotic activity is abrogated by caspase cleavage in dying T lymphocytes
Notch1 antiapoptotic activity is abrogated by caspase cleavage in dying T lymphocytes
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DOI：
10.1038/sj.cdd.4401568
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发表时间：
2005-03-01
影响因子：
12.4
通讯作者：
Sékaly, RP
中科院分区：
文献类型：
--
作者：
Cohen, LY;Bourbonnière, M;Sékaly, RP
通过 Notch1 受体的过度信号传导会抑制 T 淋巴细胞的凋亡。由于多种抗凋亡蛋白在细胞死亡过程中被 caspase 裂解，因此我们研究了 Notch1 是否是 caspase 底物。结果表明，在 Jurkat 细胞或外周 T 淋巴细胞凋亡过程中，Notch1 (NICD) 的胞内结构域被切割成 6 个片段。 Caspase 抑制剂 DEVD-fmk 和 VEID-fmk 或 Bcl-2 表达可阻止 Notch1 裂解。 Caspase-3 和 caspase-6 使用位于 NF-kappaB 结合域、锚蛋白重复序列和反式激活域内的位点将 NICD 切割成六个片段。 Notch1 裂解与凋亡 T 细胞中 HES-1 表达的丧失相关。 Notch1 片段不能抑制 T 细胞杂交瘤中激活诱导的细胞死亡，证实了 Caspases 消除了 Notch1 抗凋亡活性。 NICD（而非片段）拮抗 Nur77 活性的能力支持了该因子在 Notch1 抗凋亡功能中的作用。
Excessive signaling via the Notch1 receptor inhibits apoptosis in T lymphocytes. Since several antiapoptotic proteins are cleaved by caspases during cell death, we investigated whether Notch1 was a caspase substrate. Results demonstrate that the intracellular domain of Notch1 (NICD) is cleaved into six fragments during apoptosis in Jurkat cells or peripheral T lymphocytes. Notch1 cleavage is prevented by the caspase inhibitors DEVD-fmk and VEID-fmk or by Bcl-2 expression. Caspase-3 and caspase-6 cleave the NICD into six fragments using sites located within the NF-kappaB binding domain, the ankyrin repeats and the transactivation domain. Notch1 cleavage correlates with the loss of HES-1 expression in apoptotic T cells. Notch1 fragments cannot inhibit activation-induced cell death in a T-cell hybridoma, confirming the abrogation of Notch1 antiapoptotic activity by caspases. The ability of the NICD but not the fragments to antagonize Nur77 activity supports a role for this factor in Notch1 antiapoptotic function.