P-Glycoprotein (Pgp) is a plasma membrane protein, which functions as an efflux pump to transport multiple cytotoxic drugs out of the cell utilizing energy from ATP hydrolysis. Pgp is responsible for most cases of multidrug resistance (MDR) in tumors and thus limits the success of chemotherapy. Pgp has been shown to have high basal and drug-stimulated ATPase activity. Recent studies have shown that Pgp may have several functional states during each cycle of ATP binding, hydrolysis, and drug transport. The general goal of this application is to understand the molecular mechanism of Pgp-mediated drug transport and its relationship to the topological folding of Pgp. To achieve this general goal, we plan to accomplish the following specific aims: (1) to investigate the structural change of Pgp in its catalytic cycle; (2), to investigate the structural change of Pgp elicited by drug binding; (3) to investigate the involvement of topological change of Pgp in its function; and (4) to investigate the molecular mechanism by which ribosomes and ribosome- associated proteins determine the topological folding of Pgp. The information and probes obtained from this study will help us understand the molecular mechanism of Pgp-mediated drug transport, the relationship between the topological folding and function of Pgp, and the molecular basis of Pgp-mediated MDR. It thus will help increase the effectiveness of cancer chemotherapy. Results from this study will also help us understand how the membrane folding of mammalian polytopic membrane proteins is regulated in general. This work may lead us to the discovery of a new family of chaperone proteins associated with ribosomes that are important in determining the folding of membrane proteins co-translationally.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM059475-01
Application #
2855336
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1998-09-01
Project End
2002-08-31
Budget Start
1998-09-01
Budget End
1999-08-31
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Pharmacology
Type
Schools of Medicine
DUNS #
005436803
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Han, B; Zhang, J-T (2004) Multidrug resistance in cancer chemotherapy and xenobiotic protection mediated by the half ATP-binding cassette transporter ABCG2. Curr Med Chem Anticancer Agents 4:31-42
Xu, Junkang; Liu, Yang; Yang, Youyun et al. (2004) Characterization of oligomeric human half-ABC transporter ATP-binding cassette G2. J Biol Chem 279:19781-9
Dong, Zizheng; Liu, Lisa H; Han, Baoguang et al. (2004) Role of eIF3 p170 in controlling synthesis of ribonucleotide reductase M2 and cell growth. Oncogene 23:3790-801
Han, Baoguang; Dong, Zizheng; Zhang, Jian-Ting (2003) Tight control of platelet-derived growth factor B/c-sis expression by interplay between the 5'-untranslated region sequence and the major upstream promoter. J Biol Chem 278:46983-93
Dong, Zizheng; Zhang, Jian-Ting (2003) EIF3 p170, a mediator of mimosine effect on protein synthesis and cell cycle progression. Mol Biol Cell 14:3942-51
Han, Baoguang; Dong, Zizheng; Liu, Yang et al. (2003) Regulation of constitutive expression of mouse PTEN by the 5'-untranslated region. Oncogene 22:5325-37
Yang, Youyun; Chen, Qun; Zhang, Jian-Ting (2002) Structural and functional consequences of mutating cysteine residues in the amino terminus of human multidrug resistance-associated protein 1. J Biol Chem 277:44268-77
Han, Baoguang; Zhang, Jian-Ting (2002) Regulation of gene expression by internal ribosome entry sites or cryptic promoters: the eIF4G story. Mol Cell Biol 22:7372-84
Chen, Qun; Yang, Youyun; Liu, Yang et al. (2002) Cytoplasmic retraction of the amino terminus of human multidrug resistance protein 1. Biochemistry 41:9052-62
Pincheira, R; Chen, Q; Zhang, J T (2001) Identification of a 170-kDa protein over-expressed in lung cancers. Br J Cancer 84:1520-7

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