MGMT MODULATION IN ENVIROMENTAL CARCINOGVENESIS

Project: Research project

Project Details

Description

N-nitroso compounds are environmentally encountered by humans in
occupational settings, during food consumption and from cigarette smoke.
Many N-nitroso compounds generate mutations via alkylation damage of DNA.
All cells synthesize a protein that specifically and directly repairs the
most potent mutagenic lesion produced by monofunctional alkylating
agents, namely 06-alkylguanine (06alkylGua). Activity levels of the
repair protein, O6-methylguanine-DNA methyltransferase (MGMT), are low in
the brain compared to the liver. An inverse correlation between tumor
formation subsequent to DNA alkylation with the level of MGMT activity
has been inferred. Brain tissue, which displays low levels of MGMT
activity, is highly susceptible to tumor formation after DNA alkylation
damage. Primary brain tumors result in more deaths than Hodgkin's disease
or multiple sclerosis in adults and brain tumors may be increasing in the
elderly population. The current prognosis for patients with brain tumors
is dismal. The proposed project is designed to more clearly define the role of MGMT
in carcinogenesis and to characterize modes of regulation of MGMT gene
expression. The hypothesis that the frequency of alkylation
carcinogenesis is inversely proportional to the MGMT activity level for a
given tissue will be tested. Because of the relationship between brain
tumor formation after alkylation damage and MGMT activity, a portion of
the proposal involves generating transgenic mice that overexpress human
MGMT (hMGMT) in brain tissue. High levels of MGMT expression in brain is
assured by using the human transferrin promoter (hTF) which has
demonstrated high expression in brain tissue. hTF/MGMT transgenic mice
will be exposed to DNA alkylating agents to analyze the effects of
increased MGMT activity on tumorigenesis. As a long term goal to
determine the effects of reduced MGMT activity on tumor formation after
mutagen exposure, homologous recombination techniques will be employed
with embryonic stem (ES) cells to disrupt one copy of endogenous murine
MGMT. Disruption or alteration of one copy of MGMT should effectively
reduce MGMT activity. The molecular mechanism(s) that result in low MGMT activity in brain
relative to liver remain undefined. The hypothesis that tissue-specific
cis-acting DNA regulatory elements function to produce low MGMT activity
in brain and high MGMT activity in liver will be tested. To our
knowledge, mechanisms of transcriptional regulation for a mammalian DNA
repair gene have not yet been described. Circumstances are now
propitious for identifying cis-acting DNA regulatory elements that may
determine the levels of MGMT activity in various tissues. These
approaches will facilitate progress toward defining the role of DNA
repair genes in alkylation-induced tumor formation.
StatusFinished
Effective start/end date9/30/929/29/98

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $92,005.00
  • National Institutes of Health: $105,472.00

ASJC

  • Environmental Science(all)
  • Medicine(all)

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