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タイトル: Post-transcriptional regulation of human pregnane X receptor by micro-RNA affects the expression of cytochrome P450 3A4.
著者: Takagi, Shingo
Nakajima, Miki link image link image
Mohri, Takuya
Yokoi, Tsuyoshi link image
中嶋, 美紀
横井, 毅
発行日: 2008年 4月11日
出版社(者): American Society for Biochemistry and Molecular Biology
雑誌名: The Journal of biological chemistry
ISSN: 0021-9258
巻: 283
号: 15
開始ページ: 9674
終了ページ: 9680
抄録: Pregnane X receptor (PXR) is a major transcription factor regulating the inducible expression of a variety of transporters and drug-metabolizing enzymes, including CYP3A4 (cytochrome P450 3A4). We first found that the PXR mRNA level was not correlated with the PXR protein level in a panel of 25 human livers, indicating the involvement of post-transcriptional regulation. Notably, a potential miR-148a recognition element was identified in the 3'-untranslated region of human PXR mRNA. We investigated whether PXR might be regulated by miR-148a. A reporter assay revealed that miR-148a could recognize the miR-148a recognition element of PXR mRNA. The PXR protein level was decreased by the overexpression of miR-148a, whereas it was increased by inhibition of miR-148a. The miR-148a-dependent decrease of PXR protein attenuated the induction CYP3A4 mRNA. Furthermore, the translational efficiency of PXR (PXR protein/PXR mRNA ratio) was inversely correlated with the expression levels of miR-148a in a panel of 25 human livers, supporting the miR-148a-dependent regulation of PXR in human livers. Eventually, the PXR protein level was significantly correlated with the CYP3A4 mRNA and protein levels. In conclusion, we found that miR-148a post-transcriptionally regulated human PXR, resulting in the modulation of the inducible and/or constitutive levels of CYP3A4 in human liver. This study will provide new insight into the unsolved mechanism of the large interindividual variability of CYP3A4 expression.
DOI: 10.1074/jbc.M709382200
URI: http://hdl.handle.net/2297/10013
資料種別: Journal Article
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このアイテムを引用あるいはリンクする場合は次の識別子を使用してください。 http://hdl.handle.net/2297/10013



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