Human mismatch repair gene, MLH1, is transcriptionally repressed by the hypoxia-inducible transcription factors, DEC1 and DEC2

Oncogene 27 巻 4200-4209 頁 2008 発行
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タイトル ( eng )
Human mismatch repair gene, MLH1, is transcriptionally repressed by the hypoxia-inducible transcription factors, DEC1 and DEC2
作成者
Nakamura Hideaki
Tanimoto Keiji
Yunokawa Mayu
Kato Yukio
Yoshiga Koji
Poellinger Lorenz
Nishiyama Masahiko
収録物名
Oncogene
27
開始ページ 4200
終了ページ 4209
抄録
Tumor hypoxia has been reported to cause a functional loss in DNA mismatch repair (MMR) system as a result of down-regulation of MMR genes, although the precise molecular mechanisms remain unclear. In this study, we focused on the down-regulation of a key MMR gene, MLH1, and demonstrated that hypoxia-inducible transcription repressors, DEC1 and DEC2, participated in its transcriptional regulation via their bindings to E-box-like motif(s) in MLH1 promoter region. In all cancer cell lines examined, hypoxia increased expression of DEC1 and DEC2, known as hypoxia-inducible genes, but decreased MLH1 expression in an exposure time-dependent manner at both the mRNA and protein levels. Co-transfection reporter assay revealed that DEC1 and, to greater extent, DEC2 as well as hypoxia repressed MLH1 promoter activity. We further found that the action was remarkably inhibited by trichostatin A, and identified a possible DEC-response element in the MLH1 promoter. In vitro electrophoretic gel mobility shift and chromatin immunoprecipitation assays demonstrated that DEC1 or DEC2 directly bounds to the suggested element, and transient transfection assay revealed that overexpression of DEC2 repressed endogenous MLH1 expression in the cells. Hypoxia-induced DEC may impair MMR function through repression of MLH1 expression, possibly via the histone deacethylase (HDAC)-mediated mechanism in cancer cells.
著者キーワード
MLH1
DEC1
DEC2
hypoxia
HIF-1
NDC分類
医学 [ 490 ]
言語
英語
資源タイプ 学術雑誌論文
出版者
Nature Publishing Group
発行日 2008
権利情報
Copyright (c) 2008 Nature Publishing Group
出版タイプ Author’s Original(十分な品質であるとして、著者から正式な査読に提出される版)
アクセス権 オープンアクセス
収録物識別子
[ISSN] 0950-9232
[DOI] 10.1038/onc.2008.58
[NCID] AA10687380
[DOI] http://dx.doi.org/10.1038/onc.2008.58