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.