PROTEIN KINASE MEDIATED REGULATION OF THE AH RECEPTOR

Project: Research project

Project Details

Description

The Ah receptor (AhR) has been shown to be largely responsible for the
toxic and tumor promotional properties of 2,3,7,8- tetrachlorodibenzo-p-
dioxin (TCDD), especially in rodents. While the human population is
exposed to low levels of TCDD and related compounds, the actual long
term health effect(s) remain to be elucidated. Little is known about
the biochemical processes involved in the activation and regulation of
this ligand-activated helix-loop-helix/basic region transcriptional
factor. It is our underlying hypothesis that interspecies differences
in toxicity results from differences in the biochemical and
transcriptional regulatory pathways for the AhR and Ah receptor nuclear
translocator protein (ARNT). In this application the multiple
mechanisms of AhR regulation by protein kinases will be examined,
including the following aims; 1) Examine the mechanism(s) of protein
kinase C regulation Ah receptor-mediated gene expression, 2) Examine the
ability of MAP kinases to alter Ah receptor-mediated gene expression,
3) Characterize the ability of other protein kinase pathways and
receptor systems to influence Ah receptor-mediated gene expression. We
will utilize a variety of techniques, including AhR and ARNT constructs,
transient transfection techniques, kinase inhibitors, kinase dominant-
negative, constitutively-active and wild-type kinase constructs.
Collectively, these studies will develop an understanding of the ability
of protein kinases to regulate the activity of the Ah receptor pathway.
This information can then be used to explore developmental-, tissue-,
and species-specific differences in TCDD-mediated toxicity.
StatusFinished
Effective start/end date8/1/987/31/99

Funding

  • National Institute of Environmental Health Sciences

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