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：法尼醇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，我们试图鉴定和分析由PPAR或FXR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（FABP 6/I-BABP，IBAT）和FXR共定位于大鼠卵巢。这些基因在卵巢分化过程中表达。此外，我们已经证明人OSBa/β基因被FXR和核受体LXR（肝X受体）上调（Pharmaceutical Res.24：390-398，2007）。核受体PPAR/FXR介导的信号转导在癌发生或转移中的分析：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.肿瘤学杂志32：767-775，2008）。此外，我们已经证明FABP 6在人结肠直肠癌中上调（Clin. Cancer Res.12（17）：5090-5095，2006）。新型PPAR介导的信号转导的分析：我们发现FABP 5和FABP 7（B-FABP）在大鼠脑中的生长锥中特异性表达，这对神经变性和再生过程很重要。我们已经为每个FABP引入了siRNA，以分析它们在生长锥中的功能。此外，我们还尝试使用免疫沉淀分析来检测与FABP 5或FABP 7相互作用的特异性蛋白质。

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.