The kinesin KIF1Bβ acts downstream from EglN3 to induce apoptosis and is a potential 1p36 tumor suppressor
The kinesin KIF1Bβ acts downstream from EglN3 to induce apoptosis and is a potential 1p36 tumor suppressor
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DOI：
10.1101/gad.1648608
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发表时间：
2008-04-01
影响因子：
10.5
通讯作者：
Kaelin, William G., Jr.
中科院分区：
文献类型：
--
作者：
Schlisio, Susanne;Kenchappa, Rajappa S.;Kaelin, William G., Jr.
VHL、NF-1、c-Ret和琥珀酸脱氢酶亚基B和D作用于发育性凋亡通路，当神经生长因子（NGF）对神经元祖细胞产生限制并需要EglN3脯氨酸羟化酶作为下游效应物时，该通路被激活。这些基因的种系突变导致家族性嗜铬细胞瘤和其他神经嵴源性肿瘤。通过无偏倚shRNA筛选，我们发现激酶KIF1B β在EglN3的下游起作用，当NGF受限时，它是神经元凋亡的必要和充分条件。KIF1B β映射到染色体1p36.2，这在神经嵴源性肿瘤（包括神经母细胞瘤）中经常被删除。我们在神经母细胞瘤和嗜铬细胞瘤中发现了遗传性功能缺失的KIF1B β错义突变，在髓母细胞瘤中发现了获得性功能缺失突变，认为KIF1B β是这些缺失的致病靶标。
VHL, NF-1, c-Ret, and Succinate Dehydrogenase Subunits B and D act on a developmental apoptotic pathway that is activated when nerve growth factor (NGF) becomes limiting for neuronal progenitor cells and requires the EglN3 prolyl hydroxylase as a downstream effector. Germline mutations of these genes cause familial pheochromocytoma and other neural crest-derived tumors. Using an unbiased shRNA screen we found that the kinesin KIF1B beta acts downstream from EglN3 and is both necessary and sufficient for neuronal apoptosis when NGF becomes limiting. KIF1B beta maps to chromosome 1p36.2, which is frequently deleted in neural crest-derived tumors including neuroblastomas. We identified inherited loss-of-function KIF1B beta missense mutations in neuroblastomas and pheochromocytomas and an acquired loss-of-function mutation in a medulloblastoma, arguing that KIF1B beta is a pathogenic target of these deletions.