Fhit deficiency-induced global genome instability promotes mutation and clonal expansion.
Fhit deficiency-induced global genome instability promotes mutation and clonal expansion.
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DOI：
10.1371/journal.pone.0080730
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Huebner K
中科院分区：
文献类型：
--
作者：
Miuma S;Saldivar JC;Karras JR;Waters CE;Paisie CA;Wang Y;Jin V;Sun J;Druck T;Zhang J;Huebner K
在染色体脆性位点FRA 3B编码的Fhit表达的缺失导致复制应激增加、基因组不稳定性和遗传改变的积累。我们已经提出，Fhit是一个基因组的“看护人”，其损失启动基因组不稳定的癌前病变。我们的特点是等位基因拷贝数的变化和表达变化，观察Fhit缺陷细胞与细胞增殖和外显子突变的变化，使用细胞从小鼠胚胎成纤维细胞（MEFs），小鼠肾脏，早期和晚期后，在文化中建立，并在致癌物治疗。Fhit -/- MEFs比Fhit +/+ MEFs更快地逃避衰老而变得永生; -/- MEFs和肾培养物显示等位基因损失和获得，而+/+衍生的细胞显示很少的基因组改变。在小鼠肾-/-细胞进行性组织培养传代过程中，p53、p21、Mcl 1和活性caspase 3的表达发生了显著变化。为了确定与体内肿瘤前变化相关的基因组变化，对用致癌物7，12-二甲基苯并[a]蒽处理小鼠后的+/+和-/-肝组织以及用该致癌物体外处理的+/+和-/-肾细胞的外显子组DNA进行测序。与+/+ DNA相比，-/-外显子组DNA在更多基因中显示出小的插入、缺失和点突变，其中一些可能与癌前病变有关。因此，Fhit缺失提供了“增变因子”表型，即一种细胞环境，其中轻度基因组不稳定性允许克隆扩增，通过增殖优势和逃避凋亡，响应生存压力。
Loss of Fhit expression, encoded at chromosome fragile site FRA3B, leads to increased replication stress, genome instability and accumulation of genetic alterations. We have proposed that Fhit is a genome ‘caretaker’ whose loss initiates genome instability in preneoplastic lesions. We have characterized allele copy number alterations and expression changes observed in Fhit-deficient cells in conjunction with alterations in cellular proliferation and exome mutations, using cells from mouse embryo fibroblasts (MEFs), mouse kidney, early and late after establishment in culture, and in response to carcinogen treatment. Fhit -/- MEFs escape senescence to become immortal more rapidly than Fhit +/+ MEFs; -/- MEFs and kidney cultures show allele losses and gains, while +/+ derived cells show few genomic alterations. Striking alterations in expression of p53, p21, Mcl1 and active caspase 3 occurred in mouse kidney -/- cells during progressive tissue culture passage. To define genomic changes associated with preneoplastic changes in vivo, exome DNAs were sequenced for +/+ and -/- liver tissue after treatment of mice with the carcinogen, 7,12-dimethylbenz[a]anthracene, and for +/+ and -/- kidney cells treated in vitro with this carcinogen. The -/- exome DNAs, in comparison with +/+ DNA, showed small insertions, deletions and point mutations in more genes, some likely related to preneoplastic changes. Thus, Fhit loss provides a ‘mutator’ phenotype, a cellular environment in which mild genome instability permits clonal expansion, through proliferative advantage and escape from apoptosis, in response to pressures to survive.
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影响因子：
64.8
作者：
Bartkova, J;Horejsi, Z;Bartek, J
通讯作者：
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影响因子：
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作者：
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影响因子：
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作者：
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影响因子：
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作者：
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