Studies on Novel Nuclear Receptor-mediated Signal Transduction

为了阐明核受体FXR(法尼醇X受体)或PPAR(过氧体增殖物激活受体)介导的新的信号通路，我试图确定它们的靶基因或分析它们的功能和基因表达。在研究过程中，我已经完成了FXR靶基因，人回肠胆汁酸结合蛋白(I-BABP)基因的表达，受转录因子SREBP(类固醇反应元件结合蛋白)-1c和核受体LXR(肝脏X受体)的上调，这取决于细胞中的类固醇浓度。在寻找FXR靶基因的过程中，我发现了人低密度脂蛋白受体基因被胆汁酸反式激活的事实。广泛的分析表明，胆汁酸上调低密度脂蛋白受体基因的表达主要归因于胆汁酸通过MAP激酶级联途径稳定低密度脂蛋白受体基因，而不是通过FXR介导的途径。在寻找FXR靶基因的过程中，RANTES(肝脏激活后调节，正常T细胞表达和分泌)基因被胆汁酸激活。此外，这种上调受到PPAR配体纤毛膜的抑制。我发现核受体PPAR靶基因C-FABP(皮肤脂肪酸结合蛋白)在人类恶性前列腺癌或乳腺癌中上调，并参与这些肿瘤的转移。此外，C-FABP上调导致血管内皮细胞生长因子(VEGFm RNA)和蛋白水平升高。

To elucidate novel signaling pathways mediated by nuclear receptors, FXR (farnesoid X receptor) or PPAR (peroxysome proliferator-activated receptor), I have tried to identify their target genes or to analyze their functions and gene expressions.1. During the course of studies, I have accomplished that the FXR target gene, human I-BABP (ileal bile acid-binding protein) gene expression is up-regulated by transcription factor SREBP (sterol response element-binding protein)-1c and nuclear receptor LXR (liver X receptor) depending upon cellular sterol concentration.2. During the course of search for FXR target genes, I have found out the facts that the human LDL (low density lipoprotein) receptor gene is transactivated by bile acids. Extensive analyses showed that the up-regulation of LDL receptor gene expression by bile acids is mainly attributable to stabilization of the LDL receptor mRNA by bile acids through MAP kinase cascades but not to the FXR-mediate pathways.3. During the course of search for FXR target genes, RANTES (hepatic regulated upon activation, normal T-cell expressed and secreted) gene is activated by bile acids. Furthermore, this up-regulation is repressed by PPAR ligand, fibrates.4. I have found that the nuclear receptor PPAR target gene, C-FABP (cutaneous fatty acid-binding protein), is up-regulated in human malignant prostate or breast cancers and is involved in metastasis in these tumors. Furthermore, up-regulation of C-FABP caused increase in the levels of VEGF (vascular endothelial growth factor) mRNA and proteins.