MOLECULAR BASES OF P GLYCOPROTEIN TOPOLOGY AND FUNCTION

  • Zhang, Jian-Ting, (PI)

Project: Research project

Description

The P-glycoprotein (Pgp) is a membrane protein expressed in the plasma
membrane. It functions as an efflux pump which transports 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. Recently, Pgp has also been suggested to be
involved in cell volume regulation as a cell-swelling activated chloride
channel. How a single protein can have such different function is
unknown. My recent studies have shown that at least two distinct
topological structures of Pgp coexist in microsome membranes of a cell-
free system. Therefore, it is possible that these two structures carry the
two different Pgp functions. The general goals of this application are to define how (or if) the two
different structures of Pgp relate to the two different functions and how
this is regulated in mammalian cells. To this end, (a) Pgp molecules with
a single topological structure will be created by genetic engineering, (b)
the Cl--channel and drug-transport activities of these molecules will be
investigated, and (c) site-directed polyclonal antibodies will be raised
to analyze the membrane topology of Pgp expressed in cells. The information and probes obtained from this study will significantly
enhance our understanding of the molecular basis of multidrug resistance
and thus increase the effectiveness of cancer chemotherapy. Additionally,
this study will increase our understanding of how specific protein
topological structures are related to transport functions in general.
StatusFinished
Effective start/end date7/1/946/30/03

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $236,538.00
  • National Institutes of Health: $243,633.00

Fingerprint

P-Glycoprotein
Multiple Drug Resistance
Neoplasms
Drug Therapy
Genetic Engineering
Membranes
Cell-Free System
Microsomes
Cell Size
Chloride Channels
Pharmaceutical Preparations
Membrane Proteins
Hydrolysis
Adenosine Triphosphate
Proteins
Antibodies
Cell Membrane

ASJC

  • Medicine(all)