2005 Fiscal Year Final Research Report Summary
Interaction between endogenous mutator AID and exogenous oncogenic factors in carcinogenesis
| Project/Area Number |
16390115
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Experimental pathology
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| Research Institution | Kyoto University |
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Principal Investigator |
KINOSHITA Kazuo Kyoto University, Graduate School of Medicine, Research Associate Professor, 医学研究科, 科学技術振興助教授 (50293874)
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| Project Period (FY) |
2004 – 2005
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| Keywords | mutation / somatic hypermutation / class-switch recombination / AID / Cre recombinase |
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| Research Abstract |
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.
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