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Interaction between endogenous mutator AID and exogenous oncogenic factors in carcinogenesis

内源性突变 AID 与外源性致癌因子在致癌过程中的相互作用

基本信息

批准号：
16390115
负责人：
KINOSHITA Kazuo
金额：
$ 9.54万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

项目摘要

Exogenous chemical substance and physical factors have long been considered to be primary causes of genetic mutations associated with cancer development. However, such view is still hypothetical and lacks good experimental support. On the contrary, there is emerging hypothesis that cancer develops as a consequence of interaction between endogenous mutators and exogenous agents. Activation-induced cytidine deaminase (AID) is one of endogenous mutators. Overexpression of AID in mice causes T-cell lymphoma and lung cancer. Study of oncogenic potential of AID in other organs of this mouse model is difficult due to early death from T-cell lymphoma. To circumvent this problem, new transgenic model was created, in which temporal and spatial control of AID expression is made possible using Cre-loxP recombination system. Expression of Cre regulated by tissue-specific promoters induces excision of green fluorescent protein-coding element and expression of downstream AID gene. Such conditional AID transgenic mice (AID cTg) were crossed with CD19-Cre and TNAP-Cre mice, resulting in B cell-specific and systemically mosaic expression, respectively. Unexpectedly, B cell-specific AID expression did not cause B-cell tumor, suggesting negative regulation of overexpressed AID activity in B cells. Mosaic expression of AID caused liver and lung tumor in some individuals at 60 weeks after birth. This result suggests potential tumorigenicity of AID in other organs than T cells and lung.

长期以来，外源性化学物质和物理因素一直被认为是与癌症发展相关的基因突变的主要原因。然而，这种观点仍然是假设的，缺乏良好的实验支持。相反，有一种新的假说认为，癌症的发展是内源性突变因子和外源性因子相互作用的结果。激活诱导型胞苷脱氨酶(AID)是一种内源性突变体。在小鼠体内过度表达AID会导致T细胞淋巴瘤和肺癌。由于T细胞淋巴瘤的早期死亡，研究AID在该小鼠模型其他器官中的致癌潜力是困难的。为了解决这一问题，人们建立了新的转基因模型，利用Cre-loxP重组系统实现了对AID表达的时空调控。受组织特异性启动子调控的Cre表达可导致绿色荧光蛋白编码元件的缺失和下游AID基因的表达。将这些条件性AID转基因小鼠(AID CTG)与CD19-Cre和TnAP-Cre小鼠杂交，分别获得B细胞特异性和系统嵌合表达。出乎意料的是，B细胞特异的AID表达并没有引起B细胞肿瘤，这表明B细胞中过表达的AID活性是负调控的。在出生后60周，AID的嵌合表达在一些个体中引起了肝和肺肿瘤。这一结果提示AID在T细胞和肺以外的其他器官具有潜在的致瘤性。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Role of DNA polymerase theta in tolerance of endogenous and exogenous DNA damage in mouse B cells

DNA聚合酶theta在小鼠B细胞内源性和外源性DNA损伤耐受中的作用

DOI：
发表时间：
2006
期刊：
Genes Cells 11・2
影响因子：
0
作者：
Ukai;A.et al.
通讯作者：
A.et al.

De novo protein synthesis is required for activation-induced cytidine deaminas dependent DNA cleavage in immunoglobulin class switch recombination

免疫球蛋白类别转换重组中激活诱导的胞苷脱氨依赖性 DNA 裂解需要从头合成蛋白质

DOI：
发表时间：
2004
期刊：
Proc.Natl.Acad.Sci.U.S.A. 101・35
影响因子：
0
作者：
Begum;N.A.et al.
通讯作者：
N.A.et al.

Negative regulation of activation-induced cytidine deaminase in B cells

DOI：
10.1073/pnas.0510970103
发表时间：
2006-02-21
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
影响因子：
11.1
作者：
Muto, T;Okazaki, IM;Honjo, T
通讯作者：
Honjo, T

Separate domains of AID are required for somatic hypermutation and class-switch recombination