Notch1 is a frequent mutational target in chemically induced lymphoma in mouse.
Notch1 is a frequent mutational target in chemically induced lymphoma in mouse.
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Notch1 是化学诱导小鼠淋巴瘤的常见突变靶点。
DOI：
10.1002/ijc.23832
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发表时间：
2008
期刊：
影响因子：
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通讯作者：
Soderkvist,Peter
中科院分区：
文献类型：
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作者：
Karlsson,Anneli;Ungerback,Jonas;Rasmussen,Anna;French,JohnE;Soderkvist,Peter
在人类T系急性淋巴细胞白血病（T - ALL）和来自转基因小鼠的淋巴瘤中已经报道了激活notch1突变。我们报道notch1在化学诱导的小鼠淋巴瘤中是一个普遍和主要的突变靶点。该基因经常发生突变的区域是对蛋白质稳定性至关重要的异二聚化结构域和N端配体结合区域，以及对蛋白质降解至关重要的富含脯氨酸、谷氨酸、丝氨酸和苏氨酸的多肽（PEST）结构域。另一个基因CDC4也参与Notch1的降解，并表现出频繁的突变。异二聚化和配体结合区域的突变可能导致与配体无关的信号传导，而阻止蛋白质降解的突变导致细胞内Notch1的积累。我们使用单链构象分析（SSCA）和DNA测序分析了103例化学诱导的小鼠淋巴瘤中notch1基因的突变。在28个肿瘤中发现了导致Notch1过早截断的遗传改变，而8个在异源二聚化中发现了改变，16个在配体结合区发现了缺失。双脱氧胞苷诱导的淋巴瘤显示出notch1突变的最高频率（49%），而在丁二烯和酚酞诱导的肿瘤中，notch1突变的频率较低（分别为26%和10%）。总共检测到26个新的突变和3个先前报道的突变。该报告显示notch1是2 ',3 ' -二脱氧胞苷和丁二烯诱导淋巴瘤的一个普遍和主要的突变靶点。©2008 Wiley‐Liss, Inc。
ActivatingNotch1mutations have been reported in human T‐lineage acute lymphoblastic leukemia (T‐ALL) and lymphomas from genetically modified mice. We report thatNotch1is a prevalent and major mutational target in chemically induced mouse lymphoma. The regions of the gene that are frequently mutated are the heterodimerization domain and the N‐terminal ligand‐binding region, important for protein stability, and the polypeptide rich in proline, glutamate, serine and threonine (PEST) domains, which is critical for protein degradation. Another gene,CDC4, is also involved in Notch1 degradation and shows frequent mutations. Mutations in the heterodimerization and the ligand‐binding regions may cause ligand‐independent signaling, whereas mutations preventing protein degradation result in accumulation of intracellular Notch1. We analyzed 103 chemical‐induced mouse lymphomas for mutations in theNotch1gene using single strand conformation analysis (SSCA) and DNA sequencing. Genetic alterations resulting in premature truncation of Notch1 were identified in 28 tumors, whereas 8 revealed alterations in the heterodimerization and 16 harbored deletions in the ligand‐binding region. Dideoxycytidine‐induced lymphomas displayed the highest frequency ofNotch1mutations (49%), whereas in butadiene‐ and phenolphthalein‐induced tumors showed lower frequencies (26 and 10%, respectively). In total, 26 novel and 3 previously reported mutations were detected. This report shows thatNotch1is a prevalent and major mutational target for 2′,3′‐dideoxycytidine and butadiene‐induced lymphoma. © 2008 Wiley‐Liss, Inc.