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Efp targets 14-3-3σ for proteolysis and promotes breast tumour growth

Nature volume 417, pages 871–875 (2002)Cite this article

Abstract

Oestrogen exerts its influence on target organs through activating oestrogen receptors (ERs) and regulating downstream genes by means of their oestrogen-responsive elements. Efp, a target gene product of ERα1,2,3, is a member of the RING-finger B-box coiled-coil (RBCC) motif family4. Efp is predominantly expressed in various female organs2 as well as in breast cancers5, and is thought to be essential for oestrogen-dependent cell proliferation and organ development—Efp-disrupted mice display underdeveloped uteri and reduced oestrogen responsiveness6. Here we show that Efp is a RING-finger-dependent ubiquitin ligase (E3) that targets proteolysis of 14-3-3σ, a negative cell cycle regulator that causes G2 arrest7. We demonstrate that tumour growth of breast cancer MCF7 cells implanted in female athymic mice is reduced by treatment with antisense Efp oligonucleotide. Efp-overexpressing MCF7 cells in ovariectomized athymic mice generate tumours in the absence of oestrogen. Loss of Efp function in mouse embryonic fibroblasts results in an accumulation of 14-3-3σ, which is responsible for reduced cell growth. These data provide an insight into the cell-cycle machinery and tumorigenesis of breast cancer by identifying 14-3-3σ as a target for proteolysis by Efp, leading to cell proliferation.

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Figure 1: Inhibition of Efp expression suppresses tumour growth by MCF7 cells.
Figure 2: Efp promotes cell cycle progression and tumour growth by MCF7 cells in an oestrogen-independent manner.
Figure 3: Efp conjugates to 14-3-3σ and promotes 14-3-3σ proteolysis in a proteasome-dependent manner.
Figure 4: Efp is a RING-finger-dependent ubiquitin ligase that targets 14-3-3σ.
Figure 5: Loss of Efp function causes an accumulation of 14-3-3σ and inhibits cell proliferation.

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Acknowledgements

We thank H. Yashiroda, A. Takada, K. Okamoto, M. Kabayashi, S. Inada and T. Hishinuma for technical assistance, and B. Blumberg and K. Horie for critical reading and comments on the manuscript. This work was supported in part by grants-in-aid from the Ministry of Health, Labor and Welfare, from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Author notes

  1. Satoshi Inoue

    Present address: CREST, Japan Science and Technology Corporation, Kawaguchi, Saitama, 332-0012, Japan

  2. Tomoyuki Saito

    Present address: Pharmacological Research Department, Teikoku Hormone MFG Co. Ltd, 1604 Shimo-sakunobe, Takatsu-ku, Kawasaki, Japan

  3. Tomohiko Urano, Tomoyuki Saito, Tohru Tsukui, Masami Muramatsu and Satoshi Inoue: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, 113-8655, Bunkyo-ku, Tokyo, Japan

    Tomohiko Urano, Tomoyuki Saito, Masayo Fujita, Takayuki Hosoi, Yasuyoshi Ouchi & Satoshi Inoue

  2. Research Center for Genomic Medicine and Department of Molecular Biology, Saitama Medical School, 1397-1 Yamane, Hidaka-shi, Saitama, 350-1241, Japan

    Tohru Tsukui, Masami Muramatsu & Satoshi Inoue

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Correspondence to Satoshi Inoue.

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Urano, T., Saito, T., Tsukui, T. et al. Efp targets 14-3-3σ for proteolysis and promotes breast tumour growth. Nature 417, 871–875 (2002). https://doi.org/10.1038/nature00826

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