FUNCTIONAL ROLE OF GP150-180 IN MULTIFRUG RESISTANCE

Project: Research project

Project Details

Description

This project seeks to examine the role of gp150-180 in multidrug
resistance (MDR) and its role in the circumvention of MDR by
calcium channel blockers. A major 150-180 kDa Vinca alkaloid
(gp150-180) was identified in purified plasma membranes from
MDR cells by photoaffinity labeling. Gp150-180 exhibits cross
binding specificity for Vinca alkaloids, actinomycin D,
anthracycline antibiotics, calcium channel blockers, and
calmodulin inhibitors suggesting a central functional role in MDR
phenotype and its circumvention. The role of gp150-180 in MDR
will be tested by examining the effect of specific drug
photolabeling on cellular drug uptake and efflux, and by drug
uptake and release using membrane vesicles from MDR cells. the
role of this drug acceptor protein in circumventing MDR will be
examined by competition experiments using agents previously
shown to counteract multidrug resistance. The subcellular distribution of gp150-180 over time will be
monitored. For further characterization of drug binding sites and
exploring whether gp150-180 possesses multiple drug binding sites,
or whether it may be a family of proteins, each with specificity
for a distinct class of drugs, the protein will be purified using drug
affinity chromatographic methods. The purified gp150-180 will be
inserted into planar lipid bilayers for functional reconstitution
experiments and analyzing the role of this protein in cellular drug
accumulation. The purified gp150-180 will be used to prepare
monoclonal antibodies to define plasma membrane orientation and
drug binding sites, and to evaluate the possible
microheterogeneity of gp150-180. Detailed characterization of
drug binding sites of gp150-180 may elucidate some of the
underlying mechanisms of multidrug resistance and might lead to
the development of new compounds designed to prevent or reverse
the development of the multidrug resistant phenotype.
StatusFinished
Effective start/end date9/29/877/31/93

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $98,451.00
  • National Institutes of Health

ASJC

  • Medicine(all)

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