# REGULATION OF THE AH RECEPTOR BY PHORBOL ESTERS

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 1993 · $212,594

## Abstract

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a halogenated aromatic
hydrocarbon that is considered to be one of the most toxic synthetic
compounds known to man. Exposure to TCDD is felt to be responsible for a
cascade of human health problems, ranging from birth defects to cancer.
The biological responses to TCDD are mediated through the actions of a
regulatory gene product in the cytosol of the cell called the dioxin- or
Ah receptor (AhR). TCDD binds to the AhR initiating a series of biological
events that leads to displacement of the heat shock protein hsp90,
followed by translocation of the receptor to the nucleus. The DNA binding
or activated form of the AhR is a phosphoprotein complex composed of a
ligand binding subunit and the AhR nuclear translocator (ARNT) protein. In
studies with the CYP1A1 gene, a cognate DNA binding sequence has been
elucidated that serves as a specific cis acting element to facilitate
transcriptional activation. Therefore, the rudimentary process of ligand
binding to the AhR in cytosol facilitates a cascade of events that results
in the process of transcriptional activation. While this process resembles
that of the classical steroid-like hormone receptors, little is actually
known regarding the biological events that participate in activation of
the AhR. This application will be dedicated to understanding the cellular
events involved in the regulation of the mouse AhR in vivo.

We have recently demonstrated that by treating mice with tumor promoters
such as phorbol esters (TPA), it is possible to limit the nuclear
accumulation of the AhR, and inhibit the TCDD directed transcription of
the Cyp 1 genes. (Okino, S.T. et al., J. Biol. Chem. 267, 6991,1992). We
believe that the actions of TPA in vivo inhibit the functional properties
of the cytosolic form of the AhR. Preliminary experiments have
demonstrated that ligand binding is not affected, but TPA blocks the
ability of the activated form of the AhR to bind to the Cyp1a-1 enhancer
sequences. Experiments outlined in this application are designed to
characterize the mechanism of AhR inhibition in vivo by TPA. We will
pursue a course of investigation to examine the possibility that TPA may
interfere with the unmasking of DNA binding sites by hsp90, or interrupt
the functional properties of the ARNT protein, which is critical for
nuclear translocation and DNA binding. In addition, we will also examine
the possibility that TPA downregulates specific protein kinase C (PKC)
isozymes in a fashion concordant with the inhibition of AhR function.
However, an argument is also presented indicating that TPA may not mimic
stimulatory actions of diacylglycerol on PKC, but may function indirectly
in vivo by activating humoral factors that would then lead to a depression
in AhR function. While significant information is available regarding the
physical composition of the AhR, the above experiments should add to our
understanding of the events that control the expression of this import...

## Key facts

- **NIH application ID:** 3174857
- **Project number:** 2R01CA037139-09A2
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **SAM.gov UEI:** UYTTZT6G9DT1
- **Principal Investigator:** Robert H Tukey
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1993
- **Award amount:** $212,594
- **Award type:** 2
- **Project period:** 1984-04-01 → 1996-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3174857

## Citation

> US National Institutes of Health, RePORTER application 3174857, REGULATION OF THE AH RECEPTOR BY PHORBOL ESTERS (2R01CA037139-09A2). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3174857. Licensed CC0.

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