Dependence receptor UNC5D mediates nerve growth factor depletion-induced neuroblastoma regression.
Dependence receptor UNC5D mediates nerve growth factor depletion-induced neuroblastoma regression.
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DOI：
10.1172/jci65988
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发表时间：
2013-07
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通讯作者：
Yuyan Zhu;Yuanyuan Li;S. Haraguchi;Meng Yu;M. Ohira;T. Ozaki;A. Nakagawa;T. Ushijima;E. Isog
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文献类型：
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作者：
Yuyan Zhu;Yuanyuan Li;S. Haraguchi;Meng Yu;M. Ohira;T. Ozaki;A. Nakagawa;T. Ushijima;E. Isog
神经母细胞瘤（NB）的自发消退类似于交感神经元的发育调节的程序性细胞死亡（PCD）。退化的肿瘤细胞表达高水平的神经生长因子（NGF）受体TRKA和p75 NTR，并依赖于NGF的生存;然而，潜在的分子机制仍然难以捉摸。在这里，我们表明，UNC 5D，依赖性受体，直接靶向的p53家族成员，是高度表达的有利的NB。在人类原发性有利NB中，NGF撤除强烈上调UNC 5D、E2 F1和p53。诱导的UNC 5D被半胱天冬酶2/3切割，释放的胞内片段易位到细胞核中，并与E2 F1相互作用，选择性地反式激活促凋亡靶基因。通过添加netrin-1强烈抑制UNC 5D的裂解及其诱导凋亡。与野生型细胞相比，Unc 5d（-/-）小鼠一致表现出背根神经节神经元的显著增加和对NGF耗尽诱导的交感神经元凋亡的抵抗。我们的数据表明，UNC 5D与p53和E2 F1形成正反馈回路，以促进NB消退期间NGF依赖介导的PCD。
Spontaneous regression of neuroblastoma (NB) resembles the developmentally regulated programmed cell death (PCD) of sympathetic neurons. Regressing tumor cells express high levels of the nerve growth factor (NGF) receptors TRKA and p75NTR and are dependent on NGF for survival; however, the underlying molecular mechanism remains elusive. Here, we show that UNC5D, a dependence receptor that is directly targeted by p53 family members, is highly expressed in favorable NBs. NGF withdrawal strongly upregulated UNC5D, E2F1, and p53 in human primary favorable NBs. The induced UNC5D was cleaved by caspases 2/3, and the released intracellular fragment translocated into the nucleus and interacted with E2F1 to selectively transactivate the proapoptotic target gene. The cleavage of UNC5D and its induction of apoptosis were strongly inhibited by addition of netrin-1. Unc5d(-/-) mice consistently exhibited a significant increase in dorsal root ganglia neurons and resistance to NGF depletion-induced apoptosis in sympathetic neurons compared with wild-type cells. Our data suggest that UNC5D forms a positive feedback loop with p53 and E2F1 to promote NGF dependence-mediated PCD during NB regression.