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Article

  • The EMBO Journal (2007) 26, 1831 - 1842
  • doi:10.1038/sj.emboj.7601602

Published online: 8 March 2007

CUE domain containing 2 regulates degradation of progesterone receptor by ubiquitin–proteasome

Pei-Jing Zhang1,a, Jie Zhao1,a, Hui-Yan Li1, Jiang-Hong Man1, Kun He1, Tao Zhou1, Xin Pan1, Ai-Ling Li1, Wei-Li Gong1, Bao-Feng Jin1, Qing Xia1, Ming Yu1, Bei-Fen Shen1 and Xue-Min Zhang1

  1. Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China

Correspondence to:

Xue-Min Zhang, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Tai-Ping Road 27, Beijing 100850, China. Tel.: +86 10 66930169; Fax: +86 10 68186281; E-mail: xmzhang@nic.bmi.ac.cn

aThese authors contributed equally to this work

Received 15 November 2006; Accepted 16 January 2007

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.

  • Keywords:

    • CUEDC2,
    • interaction,
    • progesterone receptor,
    • transactivation,
    • ubiquitination