論文 - 詳細
| RRC ID | 43270 |
|---|---|
| 著者 | Takagi S, Nakajima M, Mohri T, Yokoi T. |
| タイトル | Post-transcriptional regulation of human pregnane X receptor by micro-RNA affects the expression of cytochrome P450 3A4. |
| ジャーナル | J Biol Chem |
| Abstract |
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. |
| 巻・号 | 283(15) |
| ページ | 9674-80 |
| 公開日 | 2008-4-11 |
| DOI | 10.1074/jbc.M709382200 |
| PII | S0021-9258(20)57039-7 |
| PMID | 18268015 |
| MeSH | 3' Untranslated Regions / genetics 3' Untranslated Regions / metabolism* Caco-2 Cells Cytochrome P-450 CYP3A / biosynthesis* Cytochrome P-450 CYP3A / genetics Gene Expression Regulation, Enzymologic / physiology* Humans Liver / enzymology* MicroRNAs / genetics MicroRNAs / metabolism* Pregnane X Receptor Protein Biosynthesis / physiology* Receptors, Steroid / biosynthesis* Receptors, Steroid / genetics |
| IF | 4.238 |
| 引用数 | 206 |
| WOS 分野 | BIOCHEMISTRY & MOLECULAR BIOLOGY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 4 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | Hep G2 HuH-7(RCB1366) |