Phosphorylation of retinoid X receptor suppresses its ubiquitination in human hepatocellular carcinoma.
Retinoid X receptor alpha (RXRalpha) has emerged as an important nuclear receptor involved in hepatocarcinogenesis, because its ligand suppresses the development of hepatocellular carcinoma (HCC) in both experimental and clinical studies. We have demonstrated that phosphorylation of RXRalpha at serine 260 interferes with its function and delays its degradation in cultured human HCC, leading to enhanced cellular proliferation. Here, we show that in normal liver and in nonproliferating hepatocyte cultures, RXRalpha is unphosphorylated and highly ubiquitinated, rendering it sensitive to proteasome-mediated degradation. On the other hand, phosphoserine 260 RXRalpha is resistant to ubiquitination and proteasome-mediated degradation in both human HCC tissues and a human HCC cell line, HuH7. In these tissues and cells, serine 260 is phosphorylated by mitogen-activated protein (MAP) kinase. In proliferating normal hepatocytes, similar to HCC cells, RXRalpha is also phosphorylated at serine 260 and resistant to ubiquitin-mediated degradation by proteasome, but this ubiquitination of RXRalpha is differentially regulated between HCC cells and normal hepatocytes. In proliferating hepatocytes, 9-cis retinoic acid (9cRA), a ligand to RXRalpha, suppresses MAP kinase-mediated phosphorylation and thereby enhances ubiquitination of RXRalpha, whereas it fails to exert these effects in HCC cells. In conclusion, switching of the ubiquitin/proteasome-dependent degradation of RXRalpha by phosphorylation at serine 260 may be responsible for the aberrant growth of HCC and its suppression by retinoids.
Adachi
Seiji
S
Department of Molecular Pathobiochemistry, Gifu University School of Medicine, Gifu, Japan.
Okuno
Masataka
M
Matsushima-Nishiwaki
Rie
R
Takano
Yukihiko
Y
Kojima
Soichi
S
Friedman
Scott L
SL
Moriwaki
Hisataka
H
Okano
Yukio
Y
D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D006801:Humans; D008025:Ligases / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism*; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes
D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D025801:Ubiquitin; D010768:Phosphoserine; D044763:Ubiquitin-Conjugating Enzymes; D008025:Ligases