Nl. Ge et Cj. Elferink, A DIRECT INTERACTION BETWEEN THE ARYL-HYDROCARBON RECEPTOR AND RETINOBLASTOMA PROTEIN - LINKING DIOXIN SIGNALING TO THE CELL-CYCLE, The Journal of biological chemistry, 273(35), 1998, pp. 22708-22713
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcriptio
n factor in eukaryotic cells that alters gene expression in response t
o the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (T
CDD), In 5L hepatoma cells, TCDD induces a G(1), cell cycle arrest thr
ough a mechanism that involves the AhR. The retinoblastoma tumor suppr
essor protein (pRb) controls cell cycle progression through G(1), in a
ddition to promoting differentiation, We examined whether the human Ah
R or its dimerization partner, the AhR nuclear translocator, interacts
with pRb as a basis of the TCDD-induced cell cycle arrest. In vivo an
d 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 affinit
y site lies within the N-terminal 364 amino acids of the AhR, whereas
a lower affinity binding region colocalizes with the glutamine-rich tr
ansactivation domain of the receptor. AhR ligand binding is not requir
ed for the pRb interaction per se, although immunoprecipitation experi
ments in 5L cells reveal that pRb associates preferentially with the l
iganded AhR, consistent with a requirement for ligand-induced nuclear
translocation. These observations provide a mechanistic insight into A
hR-mediated cell cycle arrest and a new perspective on TCDD-induced to
xicity.