Overexpression of Rev1 promotes the development of carcinogen-induced intestinal adenomas via accumulation of point mutation and suppression of apoptosis proportionally to the Rev1 expression level.
Overexpression of Rev1 promotes the development of carcinogen-induced intestinal adenomas via accumulation of point mutation and suppression of apoptosis proportionally to the Rev1 expression level.
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DOI：
10.1093/carcin/bgw208
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发表时间：
2017-05-01
期刊：
影响因子：
4.7
通讯作者：
Kamiya K
中科院分区：
文献类型：
--
作者：
Sasatani M;Xi Y;Kajimura J;Kawamura T;Piao J;Masuda Y;Honda H;Kubo K;Mikamoto T;Watanabe H;Xu Y;Kawai H;Shimura T;Noda A;Hamasaki K;Kusunoki Y;Zaharieva EK;Kamiya K
本研究描述了一种新的转基因Rev 1过表达转基因小鼠的产生和Rev 1表达水平在化学诱导的肿瘤发生中的作用。MNU处理后，Rev 1促进了突变，并抑制了细胞凋亡的比例过表达的水平，导致加速肿瘤的发生。癌症发展通常涉及通过易错跨损伤合成（TLS）途径对受损DNA进行诱变复制。该通路的异常激活通过促进基因突变在肿瘤发生中起作用。Rev 1控制TLS通路的功能，并且Rev 1表达水平与DNA损伤诱导的细胞毒性和致突变性相关。然而，目前还不清楚是否撤销Rev 1表达触发或促进体内肿瘤发生。在这项研究中，我们产生了一种新的Rev 1过表达转基因（Tg）小鼠，并表征其对肿瘤发生的易感性。使用N-甲基-N-亚硝基脲（MNU）诱导的小肠肿瘤模型，我们发现Rev 1的转基因表达与Rev 1表达水平成比例地加速肠腺瘤的发育;然而，单独过表达Rev 1并不会导致肠腺瘤的自发发育。在Rev 1 Tg小鼠中，MNU诱导的突变升高，而细胞凋亡被抑制。在人癌细胞系HT 1080中证实了hREV 1表达水平对MNU的细胞毒性和致突变性的影响。这些数据表明，细胞Rev 1水平的失调导致突变的积累和细胞死亡的抑制，这加速了DNA损伤剂的致瘤活性。
This study describes the generation of a novel transgenic Rev1-overexpressing transgenic mouse and the role of Rev1 expression level on chemically induced tumorigenesis. Following MNU treatment, Rev1 promoted mutagenesis and suppressed apoptosis in proportion to the level of overexpression, resulting in accelerated tumorigenesis. Cancer development often involves mutagenic replication of damaged DNA by the error-prone translesion synthesis (TLS) pathway. Aberrant activation of this pathway plays a role in tumorigenesis by promoting genetic mutations. Rev1 controls the function of the TLS pathway, and Rev1 expression levels are associated with DNA damage induced cytotoxicity and mutagenicity. However, it remains unclear whether deregulated Rev1 expression triggers or promotes tumorigenesis in vivo. In this study, we generated a novel Rev1-overexpressing transgenic (Tg) mouse and characterized its susceptibility to tumorigenesis. Using a small intestinal tumor model induced by N-methyl-N-nitrosourea (MNU), we found that transgenic expression of Rev1 accelerated intestinal adenoma development in proportion to the Rev1 expression level; however, overexpression of Rev1 alone did not cause spontaneous development of intestinal adenomas. In Rev1 Tg mice, MNU-induced mutagenesis was elevated, whereas apoptosis was suppressed. The effects of hREV1 expression levels on the cytotoxicity and mutagenicity of MNU were confirmed in the human cancer cell line HT1080. These data indicate that dysregulation of cellular Rev1 levels leads to the accumulation of mutations and suppression of cell death, which accelerates the tumorigenic activities of DNA-damaging agents.
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影响因子：
3.7
作者：
Makridakis NM;Reichardt JK
通讯作者：
Reichardt JK
DOI：
10.1073/pnas.0902175106
发表时间：
2009-06-16
影响因子：
11.1
作者：
Acharya, Narottam;Johnson, Robert E.;Prakash, Satya
通讯作者：
Prakash, Satya
影响因子：
3.8
作者：
Jansen, Jacob G.;Tsaalbi-Shtylik, Anastasia;de Wind, Niels
通讯作者：
de Wind, Niels
Rev1与致癌物诱导的肺癌的发展有关。
DOI：
10.1158/1541-7786.mcr-08-0399
发表时间：
2009-02
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Dumstorf CA;Mukhopadhyay S;Krishnan E;Haribabu B;McGregor WG
通讯作者：
McGregor WG
影响因子：
13.6
作者：
He, Xiaohong;Ye, Feng;Chen, Huaizeng
通讯作者：
Chen, Huaizeng