Open AccessPhosphorylated retinoid X receptor α loses its heterodimeric activity with retinoic acid receptor β
Author(s) -
Yoshimura Kotaro,
Muto Yoshinori,
Shimizu Masahito,
MatsushimaNishiwaki Rie,
Okuno Masataka,
Takano Yukihiko,
Tsurumi Hisashi,
Kojima Soichi,
Okano Yukio,
Moriwaki Hisataka
Publication year - 2007
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2007.00621.x
Subject(s) - retinoid x receptor , retinoid x receptor alpha , retinoid x receptor beta , retinoic acid , transfection , retinoid , retinoid x receptor gamma , biology , retinoic acid receptor , phosphorylation , microbiology and biotechnology , retinoic acid receptor alpha , biochemistry , nuclear receptor , transcription factor , gene
A malfunction in retinoid X receptor (RXR) α due to phosphorylation is associated with the development of hepatocellular carcinoma. However, the precise mechanisms by which phosphorylated RXRα loses its physiological function remain unclear. In the present study we examined whether phosphorylation of RXRα affects its dimeric activity. Fluorescence resonance energy transfer studies and immunoprecipitation assays showed that the physical interaction between RXRα and retinoic acid receptor β was impaired when 293T cells were transfected with phosphomimic mutant RXRα (T82D/S260D), whereas this interaction was activated at a level similar to wild‐type RXRα‐transfected cells when the cells were transfected with an unphosphorylated mutant RXRα (T82A/S260A). Treating the T82A/S260A‐transfected cells with retinoid resulted in a significant increase in the transcriptional activities of the retinoic acid receptor responsive element and RXR responsive element promoters, whereas these transcriptional activities did not increase in the T82D/S260D‐transfected cells. Transfection with T82A/S260A enhanced both the inhibition of cell growth and the induction of apoptosis caused by retinoid, although the T82D/S260D‐transfected cells lost their responsiveness to retinoid. Moreover, transfection with T82A/S260A caused an inhibition of cell growth and a reduction of colony‐forming ability in soft agar in HuH7 human hepatocellular carcinoma cells. These findings suggest that phosphorylation of RXRα abolishes its ability to form homodimers and heterodimers with RXR and retinoic acid receptor β, thus resulting in the loss of cell growth control and the acceleration of cancer development. In conclusion, the inhibition of RXRα phosphorylation and the restoration of its original function as a master regulator of nuclear receptors might therefore be an effective strategy for controlling cancer cell growth. ( Cancer Sci 2007; 98: 1868–1874)