PATHOLOGY OF CHEMICAL CARCINOGENISIS

  • Clawson, Gary (PI)
  • SMUCKLER, EDWARD (PI)
  • CLAWSON, GARY (PI)
  • CLAWSON, GARY (PI)
  • CLAWSON, GARY (PI)

Project: Research project

Project Details

Description

The mechanisms underlying chemically-mediated malignant transformation are
to be explored. Model systems to be used include in vivo exposure of
rodents to thioacetamide, ethionine, alkylnitrosamines, and amino azo
dyes. In vitro exposure of hepatocyte cultures to these same agents will
also be employed. Previous data show a modification of nuclear restriction
of RNA species in liver cells exposed to carcinogens, potentially
representing an initiating or a promoting event, or both. The major areas
to be investigated include: (1) an analysis of the cell-free model of
nuclear RNA transport to determine the role of high-energy bond hydrolysis
as a driving force, and to assay for the significance of both selection of
RNA species for secretion and for back-diffusion to the nucleus; (2) an
analysis of in vivo restriction in the two-stage model of
hepatocarcinogenesis to learn whether "nuclear leakage" is related to
initiation or to promotion; (3) the fidelity of the in vitro system will be
surveyed. Specific cDNA probes for messenger species (Alpha1-glycoprotein
and AlphaMu-globulin) will be used to measure messenger release in vivo and
compare these data to in vitro release following turpentine and androgenic
stimulation of male rats. Additionally, these cDNA probes will be used to
isolate the messengers in vivo and in vitro to compare splicing,
processing, and polyadenylation following the release in vivo and in vitro;
4) an attempt wil be made to purify and characterize the nuclear matrix and
nuclear envelope NTase and to define their role in transport. The
potential that these also represent an ATP driven endonuclease will be
tested. This point seems relevant to the apparent frequency of genetic
information relocation associated with oncogene expression. These
experiments will be used to test the hypothesis that malignant
transformation involves alterations in the transcription and processing of
RNA, at least as a basis for the phenotypic expression of cancer.
StatusFinished
Effective start/end date4/1/876/30/99

Funding

  • National Cancer Institute
  • National Cancer Institute
  • National Cancer Institute
  • National Cancer Institute
  • National Cancer Institute

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