CUE Domain Containing 2 (CUEDC2) Regulates Degradation Of Progesterone Receptor By Ubiquitin-proteasome

Accumulated evidence indicates that progesterone receptors (PR) are involved in proliferation of breast cancer cells and are implicated in the development of breast cancer. Moreover, PR is an important indicator of steroid hormone dependence and disease prognosis in breast cancer. The loss of PR signals development of an aggressive tumor phenotype, which is usually relative to acquiring enhanced sensitivity to growth factors. PR levels are influenced by ligand binding. After progesterone treatment, PR is extensively down-regulated by mechanisms that remain unclear.In this paper, a yeast two-hybrid screen for PR led to the identification of CUE domain containing 2 (CUEDC2), whose function is unknown. Bioinformatics analysis suggests CUEDC2 as a CUE domain-contained gene. Identified as ubiquitin binding motifs, the CUE domains are small, moderately-conserved domains of about 40 amino acid residues that are found in a variety of eukaryotic proteins. CUE domains interact with both mono- and poly-ubiquitin, and have a dual role in mono- and poly-ubiquitin recognition as well as in facilitating intramolecular monoubiquitination. Our results demonstrate that CUEDC2 interacts with PR and promotes progesterone-induced PR degradation by the ubiquitin-proteasome pathway. The inhibition of endogenous CUEDC2 by siRNA nearly abrogated the progesterone-induced degradation of PR, suggesting that CUEDC2 is involved in progesterone-induced PR ubiquitination and degradation. Moreover, we identify the sumoylation site Lys-388 of PR as the target of CUEDC2-promoted ubiquitination. CUEDC2 decreases the sumoylation while promoting ubiquitination on Lys-388 of PRB. We also show that CUEDC2 represses PR transactivation, inhibits the ability of PR to stimulate rapid MAPK activity, and impairs the effect of progesterone on breast cancer cell growth. Therefore, our results identify a key posttranslational mechanism that controls PR protein levels and for the first time provide an important insight into the function of CUEDC2 in breast cancer proliferation.