| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2002: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2001: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Research Abstract |
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.
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