CUE domain containing 2 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. In this paper, a yeast two-hybrid screen for PR led to the identification of CUE domain containing 2 (CUEDC2), whose function is unknown. 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 post-translational mechanism that controls PR protein levels and for the first time provide an important insight into the function of CUEDC2 in breast cancer proliferation.
Zhang
Pei-Jing
PJ
Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Tai-Ping Road 27, Beijing 100850, China.
Zhao
Jie
J
Li
Hui-Yan
HY
Man
Jiang-Hong
JH
He
Kun
K
Zhou
Tao
T
Pan
Xin
X
Li
Ai-Ling
AL
Gong
Wei-Li
WL
Jin
Bao-Feng
BF
Xia
Qing
Q
Yu
Ming
M
Shen
Bei-Fen
BF
Zhang
Xue-Min
XM
D048868:Adaptor Proteins, Signal Transducing; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D050505:Mutant Proteins / Q000378:metabolism; D011374:Progesterone / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017434:Protein Structure, Tertiary / Q000187:drug effects; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D025801:Ubiquitin / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C519556:CUEDC2 protein, human; D002352:Carrier Proteins; D008024:Ligands; D008565:Membrane Proteins; D050505:Mutant Proteins; D011980:Receptors, Progesterone; D025801:Ubiquitin; C097314:progesterone receptor B; D011374:Progesterone; D046988:Proteasome Endopeptidase Complex