National Library of Medicine: IGM Full Record Screen
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| TITLE: | LUNG TUMOR PROMOTION BY BHT |
| AUTHORS: | MALKINSON AM |
| AUTHOR AFFILIATION: | UNIVERSITY OF COLORADO, 4200 E NINTH AVE, C-238, DENVER, CO
80262 |
| SOURCE: | Crisp Data Base National Institutes Of Health |
| SECONDARY SOURCE ID: | CRISP/99/CA33497-14 |
| ABSTRACT: | RPROJ/CRISP The long term objective is to understand the
mechanisms by which lung tumor growth is enhanced by
non-genotoxic compounds and to identify the genes which regulate
susceptibility to this process. The food additive, butylated
hydroxytoluene (BHT), encourages the development of tumors from
previously initiated cells. The quinone methide, QM-OH, is
derived from a hydroxylated metabolite of BHT, BHT-OH, and is the
probable reactive species that promotes tumors. These metabolic
reactions occur in the bronchiolar nonciliated Clara cells, one
of the cell types from which these tumors arise. Inbred strains
vary in their susceptibility to BHT- induced lung tumor
promotion. Chronic administration of BHT to inbred mice
down-regulates the pulmonary concentrations of the alpha isozyme
of protein kinase C (PKCa) and calpain in promotion-sensitive
strains but not in promotion-resistant strains. PKC content is
inversely correlated with lung growth; low PKC concentrations are
associated with rapid lung cell proliferation. We will identify
susceptibility genes by high resolution mapping using simple
sequence length polymorphism analysis, and apply this technique
to support the hypothesis that genes which regulate BHT
metabolism, PKCa, calpain, and K-ras are candidate genes for
susceptibility. We will test whether the CYPIIB gene is also a
likely candidate gene. We will study respiratory epithelial
cells in vivo and Clara cells isolated from promotion-sensitive
vs. -resistant strains following chronic BHT exposure to: analyze
the kinetics and mechanism of calpain and PKCa down-regulation;
examine the phosphorylation status of key proteins in the K-ras
signal transduction pathway known to be regulated by PKC and
calpain; and test whether BHT treatment affects the
susceptibility to programmed cell death and ability to undergo
gap junctional intercellular communication. |
| PUBLICATION TYPES: |
Research
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| LANGUAGES: |
ENG
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| SUPPORTING AGENCY: |
U.S. DEPT. OF HEALTH AND HUMAN SERVICES; PUBLIC HEALTH SERVICE;
NATIONAL INST. OF HEALTH, NATIONAL CANCER INSTITUTE
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