Topology and Function of Human p-Glycoprotein in Multidrug Resistant Breast Cancer Cells.

Abstract

Overexpression of P-glycoprotein (Pgp) in breast and other cancers is thought to be largely responsible for the development of multidrug resistance to chemotherapy. Pgp actively extrudes various chemotherapeutic drugs out of cells and may also regulate Cl channels. The goal of our research is to investigate the relationship between Pgp structure and its multiple flinctions. Here, we examine the mechanism of generating Pgp C-terminal half topology. We conclude that (I) transmembrane segment (TM) 8 can insert in the membrane in an orientation opposite from what is predicted by hydropathy analysis, (2) the folding of TM7 may influence the membrane orientation of TM8, and (3) the mechanism by which positively-charged amino acids followi%g TM8 decrease the generation of an alternate topology is not related to the net charge of these amino acids. In addition, we describe a novel approach to examine the relationship between Pgp substrate binding and Pgp topology.

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Document Details

Document Type
Technical Report
Publication Date
Aug 01, 1997
Accession Number
ADB233428

Entities

People

  • Ernest S. Han
  • Luis Reuss

Organizations

  • University of Texas Medical Branch

Tags

DTIC Thesaurus Topics

  • Amino Acids
  • Biomedical Research
  • Breast Cancer
  • Cell Line
  • Cell-Free System
  • Cells
  • Chemistry
  • Demographic Cohorts
  • Glutamic Acid
  • Materials
  • Membranes
  • Molecules
  • Orientation (Direction)
  • Peptides
  • Substrates
  • Terminals
  • Topology

Fields of Study

  • Biology

Readers

  • Molecular Genetics
  • Oncology (Cancer Research).