Global loss of imprinting leads to widespread tumorigenesis in adult mice
Global loss of imprinting leads to widespread tumorigenesis in adult mice
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DOI：
10.1016/j.ccr.2005.09.007
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发表时间：
2005-10-01
期刊：
影响因子：
50.3
通讯作者：
Jaenisch, R
中科院分区：
文献类型：
--
作者：
Holm, TM;Jackson-Grusby, L;Jaenisch, R
印迹丢失（LOI）是指通常由来源特异性DNA甲基化赋予的单等位基因调控的丢失，通常在人类肿瘤中观察到。为了检测LOI在肿瘤发生中的作用，我们建立了一个模型，通过使用瞬时去甲基化来产生无印记的小鼠胚胎干细胞（IF-ES细胞）。源自IF-ES细胞的胚胎成纤维细胞（IF-MEF）显示TGF β抗性和减少的p19和p53表达，并在SCID小鼠中形成肿瘤。IF-MEFs表现出自发永生化，并与H-Ras在细胞转化中合作。来源于IF-ES细胞的嵌合动物在12个月内发生由注射的IF-ES细胞引起的多种肿瘤。这些数据表明，LOI单独可以使细胞易于发生肿瘤，并确定了LOI赋予的永生性降低转化阈值的途径。
Loss of imprinting (LOI), commonly observed in human tumors, refers to loss of monoallelic gene regulation normally conferred by parent-of-origin-specific DNA methylation. To test the function of LOI in tumorigenesis, we developed a model by using transient demethylation to generate imprint-free mouse embryonic stem cells (IF-ES cells). Embryonic fibroblasts derived from IF-ES cells (IF-MEFs) display TGF beta resistance and reduced p19 and p53 expression and form tumors in SCID mice. IF-MEFs exhibit spontaneous immortalization and cooperate with H-Ras in cellular transformation. Chimeric animals derived from IF-ES cells develop multiple tumors arising from the injected IF-ES cells within 12 months. These data demonstrate that LOI alone can predispose cells to tumorigenesis and identify a pathway through which immortality conferred by LOI lowers the threshold for transformation.