REGULATION OF PGP1 MRNA IN MULTIDRUG-RESISTANT CELLS

Project Details

Description

Multidrug resistance (MDR) remains one of the major obstacles to
successful chemotherapy. Although the study of MDR in the laboratory and
in the clinic has progressed at an impressive rate within the past several
years, several critical questions remain unanswered. Little is known about
the mechanism(s) regulating the genes that encode P-glycoprotein, the
putative drug efflux pump whose overexpression is, at least in part,
responsible for the resistant phenotype. Our laboratory is attempting to
define these mechanisms in normal cells during development and
differentiation as well as during the development and maintenance of the
multidrug-resistant phenotype. We propose to examine these mechanisms,
beginning with a careful dissection of the components required for the
constitutive expression of the hamster pgp1 gene. Our recent
identification of a differential utilization of transcription start sites
between drug-sensitive and drug-resistant cells suggests a mechanism for
the overexpression of pgp1 in the absence of gene amplification in
actinomycin D (ActD)-selected cells; a long-range goal of our studies is
to define such a mechanism and determine the transcriptional or post-
transcriptional factors underlying the increased expression of the pgp1
gene in MDR cells. The experiments outlined in Specific Aim 1 are directed at defining the
DNA sequence elements and protein factors required for the constitutive
expression of the hamster pgp1 gene. Ultimately, we hope to identify the
DNA and protein factors involved in the tissue-specific expression of
pgp1, using hamster liver and hepatocytes as a model system. Furthermore,
we will investigate the mechanism underlying the differential utilization
of pgp1 transcription initiation sites. In Specific Aim 2, we will further
dissect the transcriptional regulation of the pgp1 gene by examining its
expression in a cell-free transcription system, with a long-range goal of
reconstituting tissue-specific transcription in vitro. In Specific Aim 3,
we propose to investigate the role that post-transcriptional mechanisms
play in the regulation of pgp1 expression in drug-sensitive vs. drug-
resistant cells.
StatusFinished
Effective start/end date3/1/943/31/06

Funding

  • National Institutes of Health: $348,600.00
  • National Institutes of Health: $214,828.00
  • National Institutes of Health: $164,264.00
  • National Institutes of Health: $49,529.00
  • National Institutes of Health: $46,725.00
  • National Institutes of Health: $168,346.00
  • National Institutes of Health
  • National Institutes of Health: $314,985.00
  • National Institutes of Health
  • National Institutes of Health: $226,675.00
  • National Institutes of Health: $243,276.00
  • National Institutes of Health
  • National Institutes of Health: $125,961.00
  • National Institutes of Health
  • National Institutes of Health: $222,639.00

ASJC

  • Medicine(all)

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