Analysis of regulation of nuclear receptor-mediated signal transdidian by the ligand-specific transporters

为了阐明配体特异性转运蛋白在核受体（FXR：法呢醇 X 受体或 PPAR：过氧化物酶体增殖物激活受体）介导的信号转导中的功能，我们尝试鉴定和分析 PPAR 或 FXR.1 介导的新型信号转导的分子机制。核受体FXR介导的信号转导分析：在研究过程中，我们发现胆汁酸转运蛋白（FABP6/I-BABP、IBAT）和FXR在大鼠卵巢中共定位。这些基因在卵巢分化过程中表达。此外，我们已经证明人类 OSBa/β 基因被 FXR 和核受体 LXR（肝脏 X 受体）上调（Pharmaceutical Res. 24:390-398, 2007）2。核受体PPAR/FXR介导的癌变或转移信号转导分析：我们发现核受体PPAR靶基因FABP-5（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表达上调，并参与这些肿瘤的转移。 FABP-5通过其siRNA的下调引起癌症转移发生率的降低(Mt. J. Oncol. 32:767-775, 2008)。此外，我们已经证明FABP6在人类结直肠癌中上调(Clin.Cancer Res.12(17):5090-5095, 2006)。3。新型PPAR介导的信号转导分析：我们发现FABP5和FABP7（B-FABP）在大鼠大脑的生长锥中特异性表达，对于神经退行性变和再生过程至关重要。我们为每个 FABP 引入了 siRNA，以分析它们在生长锥中的功能。此外，我们尝试使用免疫沉淀测定来检查与 FABP5 或 FABP7 相互作用的特定蛋白质。

To elucidate function of ligand-specific transporters in the nuclear receptor (FXR: farnesoid X receptor or PPAR: peroxysome proliferator-activated receptor)-mediated signal transduction, we have tried to identify and analyze molecular mechanisms of a novel signal transduction mediated by PPAR or FXR.1. Analysis of nuclear receptor FXR-mediated signal transduction:During the course of studies, we have revealed that bile acid transporters (FABP6/I-BABP, IBAT) and FXR are co-localized in the rat ovary. These genes are expressed during the ovary differentiation. Furthermore, we have demonstrated that human OSBa/β gene is up-regulated by FXR and nuclear receptor LXR (liver X receptor) (Pharmaceutical Res. 24:390-398, 2007)2. Analysis of nuclear receptors PPAR/FXR-mediated signal transduction in carcinogenesis or metastasis:We have found that the nuclear receptor PPAR target gene, FABP-5 (C-FABP: cutaneous fatty acid-binding protein), is up-regulated in human malignant prostate or breast cancers and that is involved in metastasis in these tumors. Down-regulation of FABP-5 by its siRNA caused decrease in the incidence of cancer metastasis (Mt. J. Oncol. 32:767-775, 2008). Furthermore, we have demonstrated that FABP6 is up-regulated in human colorectal cancers (Clin. Cancer Res. 12 (17):5090-5095, 2006).3. Analysis of novel PPAR-mediated signal transduction:We have found that FABP5 and FABP7 (B-FABP) are specifically expressed in the growth cone in the rat brain important for the neurodegeneration and regeneration process. We have introduced siRNA for each FABP to analyze their functions in the growth cone. Furthermore, we have tried to examine specific proteins interacting with FABP5 or FABP7 using the immunoprecipitation assay.