NEGATIVE REGULATION OF THE YEAST MRP, YCF1P, AND THE HUMAN MRPS BY CK2

CK2 对酵母 MRP、YCF1P 和人类 MRPS 的负调节

• 批准号: 8168250
• 负责人: Christian M Paumi
• 金额: $ 23.25万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8168250
• 关键词: ABCC1 gene; ATP-Binding Cassette Transporters; Arsenic; Cadmium; Casein Kinase 2alpha; Casein Kinase 2alpha' ; Cells; Computer Retrieval of Information on Scientific Projects Database; Cystic Fibrosis; Disease; Employee Strikes; Funding; Glutathione; Goals; Grant; Heavy Metals; Human; Institution; Lead; Malignant Neoplasms; Mercury; Metabolic; Multi-Drug Resistance; Multidrug Resistance-Associated Proteins; N-terminal; Pharmaceutical Preparations; Phosphotransferases; Play; Protein Kinase; Pseudoxanthoma Elasticum; Quality Control; Regulation; Research; Research Personnel; Resources; Role; S100A12 gene; Source; Toxic Environmental Substances; United States National Institutes of Health; Work; Yeasts; casein kinase II; effective therapy; in vivo; insight; interest; protein function

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The multidrug resistance-associated protein (MRP) subfamily of the ATP-binding cassette (ABC) transporters plays a key role in protecting cells from drugs and environmental toxins such as heavy metals (mercury, arsenic, lead, and cadmium). The MRPs (also called ABCCs) are distinguished from other ABC transporters by two striking hallmarks: 1) they contain an additional "N-terminal extension" with a conserved region called L0, and 2) they transport substrates in the form of glutathione (GSH)-conjugates. The overall goal of this work is to determine how MRP function is regulated in vivo. Specifically, I am interested in defining the role of MRP-protein kinase interactors in regulating MRP function. The aims if this proposal are identifying the mechanism by which an MRP-protein kinase interactor, the yeast casein kinase 2 (CK2) alpha subunit, Cka1p, negatively regulates the function of the yeast MRP, Ycf1p. Cka1p has been shown to be catalytically active as a homodimer and a heterodimer with the CK2 alpha' subunit, Cka2. Therefore this proposal will determine if Cka1p regulation ofYcf1p function requires Cka2p. In addition the Paumi lab will examine the role of the homologous human kinase, CKalpha in regulating human MRP1 and MRP6 function. The studies described within this proposal will provide useful insight into the role of kinases in the regulation of MRP function, the role of the MRPs in "metabolic quality control," and have the potential to establish new and more effective treatments for MRP related diseases such as cystic fibrosis, multidrug resistance in cancer, and pseudoxanthoma elasticum.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 多药耐药相关蛋白(MRP)亚家族的三磷酸腺苷结合盒(ABC)转运体在保护细胞免受药物和环境毒素(如汞、砷、铅和镉)的伤害方面发挥着关键作用。MRP(也称为ABCC)与其他ABC转运蛋白有两个显著的区别：1)它们含有一个额外的“N-末端延伸”，带有一个称为L0的保守区；2)它们以谷胱甘肽(GSH)结合物的形式运输底物。这项工作的总体目标是确定MRP功能在体内是如何调节的。具体地说，我感兴趣的是确定MRP-蛋白激酶相互作用因子在调节MRP功能中的作用。这项建议的目的是确定MRP-蛋白激酶相互作用因子酵母酪蛋白激酶2(CK2)α亚基Cka1p对酵母MRP Ycf1p功能的负面调节机制。Cka1p作为CK2α‘亚基Cka2的同源二聚体和异源二聚体具有催化活性。因此，这一建议将决定Cka1p对Ycf1p功能的调控是否需要Cka2p。此外，Paumi实验室还将研究同源人类激酶CKalpha在调节人类MRP1和MRP6功能中的作用。这项提案中描述的研究将提供有用的洞察，了解激酶在调节MRP功能中的作用，MRP在“代谢质量控制”中的作用，并有可能为囊性纤维化、癌症多药耐药和弹性假黄瘤等MRP相关疾病建立新的、更有效的治疗方法。