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J Biol Chem, Vol. 273, Issue 35, 22708-22713, August 28, 1998
From the Institute of of Chemical Toxicology, Wayne State
University, Detroit, Michigan 48201
The aryl hydrocarbon receptor (AhR) is a
ligand-activated transcription factor in eukaryotic cells that alters
gene expression in response to the environmental contaminant
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In 5L hepatoma
cells, TCDD induces a G1 cell cycle arrest through a
mechanism that involves the AhR. The retinoblastoma tumor suppressor
protein (pRb) controls cell cycle progression through G1 in
addition to promoting differentiation. We examined whether the human
AhR or its dimerization partner, the AhR nuclear translocator,
interacts with pRb as a basis of the TCDD-induced cell cycle arrest.
In vivo and in vitro assays reveal a direct interaction between pRb and the AhR but not the AhR nuclear
translocator protein. Binding between the AhR and pRb occurs through
two distinct regions in the AhR. A high affinity site lies within the
N-terminal 364 amino acids of the AhR, whereas a lower affinity binding
region colocalizes with the glutamine-rich transactivation domain of the receptor. AhR ligand binding is not required for the pRb
interaction per se, although immunoprecipitation
experiments in 5L cells reveal that pRb associates preferentially with
the liganded AhR, consistent with a requirement for ligand-induced
nuclear translocation. These observations provide a mechanistic insight
into AhR-mediated cell cycle arrest and a new perspective on
TCDD-induced toxicity.
A Direct Interaction between the Aryl Hydrocarbon Receptor and
Retinoblastoma Protein
LINKING DIOXIN SIGNALING TO THE CELL CYCLE
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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