論文 - 詳細
| RRC ID | 38900 |
|---|---|
| 著者 | Shizu R, Abe T, Benoki S, Takahashi M, Kodama S, Miayata M, Matsuzawa A, Yoshinari K. |
| タイトル | PXR stimulates growth factor-mediated hepatocyte proliferation by cross-talk with the FOXO transcription factor. |
| ジャーナル | Biochem J |
| Abstract |
Growth factor-mediated hepatocyte proliferation is crucial in liver regeneration and the recovery of liver function after injury. The nuclear receptor, pregnane X receptor (PXR), is a key transcription factor for the xenobiotic-induced expression of genes associated with various liver functions. Recently, we reported that PXR activation stimulates xenobiotic-induced hepatocyte proliferation. In the present study, we investigated whether PXR activation also stimulates growth factor-mediated hepatocyte proliferation. In G0 phase-synchronized, immortalized mouse hepatocytes, serum or epidermal growth factor treatment increased cell growth and this growth was augmented by the expression of mouse PXR and co-treatment with pregnenolone 16α-carbonitrile (PCN), a PXR ligand. In a liver regeneration model using carbon tetrachloride, PCN treatment enhanced the injury-induced increase in the number of Ki-67-positive nuclei as well as Ccna2 and Ccnb1 mRNA levels in wild-type (WT) but not Pxr-null mice. Chronological analysis of this model demonstrated that PCN treatment shifted the maximum cell proliferation to an earlier time point and increased the number of M-phase cells at those time points. In WT but not Pxr-null mice, PCN treatment reduced hepatic mRNA levels of genes involved in the suppression of G0/G1- and G1/S-phase transition, e.g. Rbl2, Cdkn1a and Cdkn1b. Analysis of the Rbl2 promoter revealed that PXR activation inhibited its Forkhead box O3 (FOXO3)-mediated transcription. Finally, the PXR-mediated enhancement of hepatocyte proliferation was inhibited by the expression of dominant active FOXO3 in vitro. The results of the present study suggest that PXR activation stimulates growth factor-mediated hepatocyte proliferation in mice, at least in part, through inhibiting FOXO3 from accelerating cell-cycle progression. |
| 巻・号 | 473(3) |
| ページ | 257-66 |
| 公開日 | 2016-2-1 |
| DOI | 10.1042/BJ20150734 |
| PII | BJ20150734 |
| PMID | 26574435 |
| MeSH | Animals Cell Cycle Cell Proliferation* Cells, Cultured Cyclin A1 / genetics Cyclin A1 / metabolism Cyclin A2 / genetics Cyclin A2 / metabolism Epidermal Growth Factor / metabolism* Forkhead Box Protein O3 Forkhead Transcription Factors / genetics Forkhead Transcription Factors / metabolism* Hepatocytes / cytology* Hepatocytes / metabolism Liver / cytology Liver / metabolism Male Mice Mice, Inbred C57BL Pregnane X Receptor Pregnenolone Carbonitrile / metabolism Receptors, Steroid / genetics Receptors, Steroid / metabolism* |
| IF | 4.097 |
| 引用数 | 8 |
| 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 | X(Twitter) |
| 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 | 293(RCB1637) |