Understanding HNF-1β through Identification of Interacting Proteins and Target Genes in the Kidney
dc.contributor.advisor | Igarashi, Peter | en |
dc.creator | Choi, Yun-Hee | en |
dc.date.accessioned | 2010-11-02T18:11:19Z | |
dc.date.available | 2010-11-02T18:11:19Z | |
dc.date.issued | 2010-11-02 | |
dc.description.abstract | Hepatocyte nuclear factor-1Beta (HNF-1Beta) is a POU/homeodomain-containing transcription factor that regulates tissue-specific gene expression in the liver, kidney, pancreas, and other epithelial organs. During kidney development, HNF-1Beta is expressed in renal collecting ducts and all segments of the nephron. Mutation of HNF-1Beta causes maturity-onset diabetes of the young type 5 (MODY5) and kidney developmental anomalies including renal agenesis, hypoplasia, and cysts. Here, I studied interacting proteins and target genes to understand the function of HNF-1Beta in the kidney. Yeast two-hybrid screening was performed to identify binding partners of HNF-1Beta in the kidney. Zyxin and LPP were isolated as putative interacting proteins. The LIM-containing proteins, Zyxin and LPP, are focal adhesion proteins that shuttle between the cytoplasm and nucleus and play a role in the architectural organization of cells. Both Zyxin and LPP interact with HNF-1Beta and stimulate the transcriptional activity of HNF-1Beta in mIMCD3 renal epithelial cells. Epidermal growth factor (EGF), which plays a role in the progression of polycystic kidney disease, induces translocation of zyxin into the nucleus. These studies identify a novel pathway by which signals may be transmitted from the cell surface to regulate the activity of a nuclear transcription factor that is essential for epithelial differentiation in the kidney. Chromatin immunoprecipitaion and DNA chip analysis (ChIP-chip) were performed to identify direct target genes of HNF-1Beta in the kidney. Phosphodiesterase 4C (PDE4C) was identified as an HNF-1Beta target gene. PDE4C belongs to the phosphodiesterase superfamily of enzymes that control the intracellular concentration of cyclic adenosine monophosphate (cAMP) by catalyzing its hydrolysis. cAMP may play a role in cystogenesis by stimulating fluid secretion and cell proliferation. PDE4C is transcriptionally activated by HNF-1Beta and regulates cAMP levels in mIMCD3 renal epithelial cells. Antibody staining showed that PDE4C is localized in the primary cilium and there interacts with a protein complex containing AKAP150, adenylyl cyclase 5/6 (AC5/6), protein kinase A (PKA), and polycystin-2 (PKD2). These results identify a cAMP-regulating protein complex that is localized in the primary cilium and is disrupted in PKD. | en |
dc.identifier.oclc | 743217936 | |
dc.identifier.uri | https://hdl.handle.net/2152.5/803 | |
dc.language.iso | en | en |
dc.subject | Cyclic AMP Receptor Protein | en |
dc.subject | Polycystic Kidney Diseases | en |
dc.subject | Hepatocyte Nuclear Factor 1-beta | en |
dc.title | Understanding HNF-1β through Identification of Interacting Proteins and Target Genes in the Kidney | en |
dc.type | Thesis | en |
dc.type.material | Text | en |
thesis.date.available | 2012-09-20 | |
thesis.degree.department | Graduate School of Biomedical Sciences | en |
thesis.degree.discipline | Genetics and Development | en |
thesis.degree.grantor | UT Southwestern Medical Center | en |
thesis.degree.level | Doctoral | en |
thesis.degree.name | Doctor of Philosophy | en |
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