Characterization of the cleaved carboxy-terminal tail of Polycysin-1

Polycysin-1 切割羧基末端尾部的表征

• 批准号: 7753708
• 负责人: David M Merrick
• 金额: $ 4.62万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7753708
• 关键词: Affect; Apoptosis; Apoptotic; Autosomal Dominant Polycystic Kidney; Binding; Biological Assay; C-terminal; Cell Culture System; Cell Culture Techniques; Cell Line; Cell Nucleus; Cell Proliferation; Cells; Cleaved cell; Co-Immunoprecipitations; Complex; Confocal Microscopy; Cyst; Cystic kidney; DNA Binding Domain; Data; Defect; Development; Dialysis procedure; Dominant-Negative Mutation; E1A-associated p300 protein; EP300 gene; Elements; Employee Strikes; End stage renal failure; Epithelial Cells; Event; Generations; Genetic Screening; Genetic Transcription; Growth; Health; Hereditary Disease; Immunoprecipitation; Immunosuppressive Agents; In Vitro; Individual; Integral Membrane Protein; Kidney; Kidney Failure; Kidney Transplantation; Lead; Libraries; Life; Link; Luciferases; Measurement; Measures; Mediating; Methods; Molecular; Morbidity - disease rate; Morphology; Mus; Mutation; Notch Signaling Pathway; Nuclear; Nuclear Translocation; Organ; Pathway interactions; Patients; Pharmaceutical Preparations; Physiological; Polycystic Kidney Diseases; Procedures; Proteins; RNA Polymerase II; Regulation; Reporter; Reporting; Risk; Role; Screening procedure; Sepharose; Signal Pathway; Signal Transduction; Staging; Stress; Suspension substance; Suspensions; Tail; Testing; Time; Transplant Recipients; Transplantation; cell growth; domain mapping; extracellular; genetic regulatory protein; histone acetyltransferase; matrigel; mortality; polycystic kidney disease 1 protein; promoter; research study; response; scaffold; small hairpin RNA; small molecule; transcription factor; vector

DESCRIPTION (provided by applicant): Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder, affecting 1 in 1000 individuals, and results in the progressive development of renal cysts, often leading to end-stage kidney failure. 85 percent of patients with ADPKD are found to have mutations in Polycystin-1 (PC-1), a large 11-transmembrane protein with a short cytoplasmic C-terminal tail. Our lab and others have documented cleavage and nuclear translocation of this C-terminal tail (referred to as p200). A hallmark of cystic growth is increased cellular proliferation and apoptosis. Several lines of evidence indicate that PC-1 inhibits cell proliferation through regulation of the Tcf-mediated Wnt signaling pathway. Furthermore, a genetic screen for transcription factors regulated by p200 highlighted several candidates, including Ddit3, and TAZ1. Ddit3 coordinates the apoptotic response to ER stress. Inactivation of TAZ in mice results in the development of polycystic kidney disease. The signaling pathways involving each of these proteins are coordinated through the transcriptional co-activating protein p300. Taken together, these data suggest the hypothesis that p200 regulates proliferation (Tcf), apoptosis (Ddit3) and cystogensis (TAZ1) in conjunction with the transcriptial regulatory protein p300. Luciferase assays will be empolyed to measure the regulatory effects of p200 on Tcf, Ddit3 and TAZ1 signaling. Direct interactions will be assessed using immunoprecipitation experiments. Finally, an in-vitro 3D cell culture system will be used to determine the phenotypic effects of p200 on these signaling pathways. Relevance Autosomal Dominant Polycystic Kidney Disease (ADPKD) is one of the most cornmon life-threatening genetic disorders and, among other complications, can ultimately leads to end-stage renal failure. Currently, the only available treatments for ADPKD is are supportive, including dialysis and kidney transplant,.Transplant patients for which patientsmust often wait years on the transplant list before receiving an organ, and then must take life-long immunosuppressive medications, which carry their own health risks. Our lab is investigating the molecular defects responsible for ADPKD, and how they relate to signaling events that control cell-growth. An understanding of these mechanisms may lead to the discovery of small molecule therapies that could reduce the growth of cysts in ADPKD patients, reducing or eliminating their need for dialysis or kidney transplant and the morbidity/mortality associated with this these procedures.

描述（由申请人提供）：常染色体显性多囊肾病（ADPKD）是一种常见的遗传性疾病，每1000个人中就有1人患病，导致肾囊肿的进行性发展，通常导致终末期肾衰竭。85%的ADPKD患者被发现在多囊蛋白-1 （PC-1）中有突变，多囊蛋白-1是一种大的11-跨膜蛋白，具有短的细胞质c端尾部。我们的实验室和其他人已经记录了这个c端尾巴（称为p200）的切割和核易位。