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Regulation of the p21WAF1 gene promoter in response to clinially relevant doses of radiation
https://repo.qst.go.jp/records/63579
https://repo.qst.go.jp/records/635791f8e4a26-e574-4062-9902-b510d2804b18
| Item type | 会議発表用資料 / Presentation(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2009-10-02 | |||||
| タイトル | ||||||
| タイトル | Regulation of the p21WAF1 gene promoter in response to clinially relevant doses of radiation | |||||
| 言語 | ||||||
| 言語 | eng | |||||
| 資源タイプ | ||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_c94f | |||||
| 資源タイプ | conference object | |||||
| アクセス権 | ||||||
| アクセス権 | metadata only access | |||||
| アクセス権URI | http://purl.org/coar/access_right/c_14cb | |||||
| 著者 |
Nenoi, Mitsuru
× Nenoi, Mitsuru× Nakajima, Tetsuo× Bing, Wang× 根井 充× 中島 徹夫× 王 冰 |
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| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | p53 is a transcription factor which plays important roles in cellular responses to various doses of ionizing radiation (IR). It is, therefore, crucial to use the actually relevant doses of IR to investigate the molecular mechanisms for the particular p53-mediated cellular responses. P21WAF1 is one of the p53 target genes functioning in cell cycle checkpoint regulation. Induction of p21WAF following exposure to IR correlates with IR sensitivity. Xenografts established from p21WAF1-deficient tumor cells have been shown to be significantly radiosensitive. In addition, treatment of cancer cells with antisense oligonucleotides targeting p21WAF1 was shown to result in the loss of G1 arrest and enhanced apoptosis. Thus, elucidation of the detailed mechanisms of IR-induction of P21WAF1 is a promising approach for uncovering novel targets of IR-mediated cancer gene therapy. It is interesting to note that p53 functions in regulation of some of its target genes by cooperating with other transcription factors. For instance, Sp1, GKLF, Ets1, and IRF-1 have been reported to be involved in transcriptional activation of p21WAF1 following exposure to UV light or ectopic overexpression of p53. However, involvement of such cooperation transcription factors in regulation of p53-target genes following exposure to IR is poorly understood. This is primarily because transiently transfected reporter vectors containing the p53 target gene promoter are much less responsive to IR than the endogenous gene; robust response usually requires the use of hyperlethal IR doses. In the present study, we carried out a comprehensive reporter gene analysis after the clinically relevant doses of IR using the adeno-associated virus-mediated reporter system which we have recently shown to be highly responsive to IR. It was shown that binding of a transcription factor Oct-1 to its recognition sequences at – 1.1kb and 1.8kb was necessary to induce the p21WAF1 gene promoter. In addition, stable transfection of cells with the Oct-1-specific siRNA suppressed both the basal and the IR-inducible components of the p21WAF1 gene expression. These results demonstrate that Oct-! plays a cooperative role in p53-mediated regulation of the p21WAF gene after irradiation. In cancer gene therapy, restriction of antitumor transgene expression in a radiation field by use of IR-inducible promoters is one of the promising approaches for tumor-specific gene delivery. Then, we investigated potential usability of the rAAV vector system in clinical application. Herpes simplex virus type-1 thymidine kinase (HSVtk) is a suicide gene, which has been shown to be effective for controlling tumor growth in animal models in combination with a prodrug ganciclovir(GCV). When tumor cells were transduced with the p21WAF1 gene promoter-driven HSVtk gene by rAAV vector, we found that the cells were significantly sensitized to repetitive treatment with 1 Gy of IR in the presence of GCV. It was therefore considered that the p21WAF1 gene promoter in combination with a rAAV vector is of potential application to the development of a low-dose IR-inducible vector for cancer gene therapy. |
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| 会議概要（会議名, 開催地, 会期, 主催者等） | ||||||
| 内容記述タイプ | Other | |||||
| 内容記述 | The 7th Japan-France Workshop on Radiation Biology | |||||
| 発表年月日 | ||||||
| 日付 | 2008-10-16 | |||||
| 日付タイプ | Issued | |||||
