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

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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.