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14-3-3σ controls mitotic translation to facilitate cytokinesis

Nature volume 446, pages 329–332 (2007)Cite this article

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Abstract

14-3-3 proteins are crucial in a wide variety of cellular responses including cell cycle progression, DNA damage checkpoints and apoptosis. One particular 14-3-3 isoform, σ, is a p53-responsive gene, the function of which is frequently lost in human tumours, including breast and prostate cancers as a result of either hypermethylation of the 14-3-3σ promoter or induction of an oestrogen-responsive ubiquitin ligase that specifically targets 14-3-3σ for proteasomal degradation1,2,3,4,5,6,7,8,9. Loss of 14-3-3σ protein occurs not only within the tumours themselves but also in the surrounding pre-dysplastic tissue (so-called field cancerization), indicating that 14-3-3σ might have an important tumour suppressor function that becomes lost early in the process of tumour evolution3,9. The molecular basis for the tumour suppressor function of 14-3-3σ is unknown. Here we report a previously unknown function for 14-3-3σ as a regulator of mitotic translation through its direct mitosis-specific binding to a variety of translation/initiation factors, including eukaryotic initiation factor 4B in a stoichiometric manner. Cells lacking 14-3-3σ, in marked contrast to normal cells, cannot suppress cap-dependent translation and do not stimulate cap-independent translation during and immediately after mitosis. This defective switch in the mechanism of translation results in reduced mitotic-specific expression of the endogenous internal ribosomal entry site (IRES)-dependent form of the cyclin-dependent kinase Cdk11 (p58 PITSLRE), leading to impaired cytokinesis, loss of Polo-like kinase-1 at the midbody, and the accumulation of binucleate cells. The aberrant mitotic phenotype of 14-3-3σ-depleted cells can be rescued by forced expression of p58 PITSLRE or by extinguishing cap-dependent translation and increasing cap-independent translation during mitosis by using rapamycin. Our findings show how aberrant mitotic translation in the absence of 14-3-3σ impairs mitotic exit to generate binucleate cells and provides a potential explanation of how 14-3-3σ-deficient cells may progress on the path to aneuploidy and tumorigenesis.

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Figure 1: 14-3-3σ binds to its targets during mitosis.
Figure 2: 14-3-3σ knockdown cells fail to suppress cap-dependent translation during and immediately after mitosis.
Figure 3: Depletion of 14-3-3σ results in impaired cytokinesis.
Figure 4: Depletion of 14-3-3σ blocks IRES-dependent mitotic translation of p58 PITSLRE kinase and results in failure of Plk1 to localize at the midbody.

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  • 11 April 2007

    The name Steven A. Artim has been corrected to Stephen C. Artim

References

  1. Vercoutter-Edouart, A. S. et al. Proteomic analysis reveals that 14-3-3σ is down-regulated in human breast cancer cells. Cancer Res. 61, 76–80 (2001)

    CAS  PubMed  Google Scholar 

  2. Ferguson, A. T. et al. High frequency of hypermethylation at the 14-3-3σ locus leads to gene silencing in breast cancer. Proc. Natl Acad. Sci. USA 97, 6049–6054 (2000)

    Article  ADS  CAS  Google Scholar 

  3. Umbricht, C. B. et al. Hypermethylation of 14-3-3σ (stratifin) is an early event in breast cancer. Oncogene 20, 3348–3353 (2001)

    Article  CAS  Google Scholar 

  4. Urano, T. et al. Efp targets 14-3-3σ for proteolysis and promotes breast tumour growth. Nature 417, 871–875 (2002)

    Article  ADS  CAS  Google Scholar 

  5. Moreira, J. M., Gromov, P. & Celis, J. E. Expression of the tumor suppressor protein 14-3-3σ is down-regulated in invasive transitional cell carcinomas of the urinary bladder undergoing epithelial-to-mesenchymal transition. Mol. Cell. Proteomics 3, 410–419 (2004)

    Article  CAS  Google Scholar 

  6. Iwata, N. et al. Frequent hypermethylation of CpG islands and loss of expression of the 14-3-3σ gene in human hepatocellular carcinoma. Oncogene 19, 5298–5302 (2000)

    Article  CAS  Google Scholar 

  7. Suzuki, H. et al. Inactivation of the 14-3-3σ gene is associated with 5′ CpG island hypermethylation in human cancers. Cancer Res. 60, 4353–4357 (2000)

    CAS  PubMed  Google Scholar 

  8. Villaret, D. B. et al. Identification of genes overexpressed in head and neck squamous cell carcinoma using a combination of complementary DNA subtraction and microarray analysis. Laryngoscope 110, 374–381 (2000)

    Article  CAS  Google Scholar 

  9. Gasco, M. et al. Coincident inactivation of 14-3-3σ and p16INK4a is an early event in vulval squamous neoplasia. Oncogene 21, 1876–1881 (2002)

    Article  CAS  Google Scholar 

  10. Prescott, A. R. Synthesis of RNA and protein during mitosis in mammalian tissue culture cells. Exp. Cell Res. 26, 260–268 (1962)

    Article  Google Scholar 

  11. Pyronnet, S., Dostie, J. & Sonenberg, N. Suppression of cap-dependent translation in mitosis. Genes Dev. 15, 2083–2093 (2001)

    Article  CAS  Google Scholar 

  12. Pyronnet, S., Pradayrol, L. & Sonenberg, N. A cell cycle-dependent internal ribosome entry site. Mol. Cell 5, 607–616 (2000)

    Article  CAS  Google Scholar 

  13. Qin, X. & Sarnow, P. Preferential translation of internal ribosome entry site-containing mRNAs during the mitotic cycle in mammalian cells. J. Biol. Chem. 279, 13721–13728 (2004)

    Article  CAS  Google Scholar 

  14. Brasey, A. et al. The leader of human immunodeficiency virus type 1 genomic RNA harbors an internal ribosome entry segment that is active during the G2/M phase of the cell cycle. J. Virol. 77, 3939–3949 (2003)

    Article  CAS  Google Scholar 

  15. Kullmann, M., Gopfert, U., Siewe, B. & Hengst, L. B. ELAV/Hu proteins inhibit p27 translation via an IRES element in the p27 5′UTR. Genes Dev. 16, 3087–3099 (2002)

    Article  CAS  Google Scholar 

  16. Hershey, J. W. Expression of initiation factor genes in mammalian cells. Biochimie 76, 847–852 (1994)

    Article  CAS  Google Scholar 

  17. Holcik, M. & Sonenberg, N. Translational control in stress and apoptosis. Nature Rev. Mol. Cell Biol. 6, 318–327 (2005)

    Article  CAS  Google Scholar 

  18. Merrick, W. C. Cap-dependent and cap-independent translation in eukaryotic systems. Gene 332, 1–11 (2004)

    Article  CAS  Google Scholar 

  19. Rogers, G. W., Richter, N. J. & Merrick, W. C. Biochemical and kinetic characterization of the RNA helicase activity of eukaryotic initiation factor 4A. J. Biol. Chem. 274, 12236–12244 (1999)

    Article  CAS  Google Scholar 

  20. Neef, R. et al. Phosphorylation of mitotic kinesin-like protein 2 by polo-like kinase 1 is required for cytokinesis. J. Cell Biol. 162, 863–875 (2003)

    Article  CAS  Google Scholar 

  21. Liu, X., Zhou, T., Kuriyama, R. & Erikson, R. L. Molecular interactions of Polo-like-kinase 1 with the mitotic kinesin-like protein CHO1/MKLP-1. J. Cell Sci. 117, 3233–3246 (2004)

    Article  CAS  Google Scholar 

  22. Beretta, L., Gingras, A. C., Svitkin, Y. V., Hall, M. N. & Sonenberg, N. Rapamycin blocks the phosphorylation of 4E-BP1 and inhibits cap-dependent initiation of translation. EMBO J. 15, 658–664 (1996)

    Article  CAS  Google Scholar 

  23. Li, T., Inoue, A., Lahti, J. M. & Kidd, V. J. Failure to proliferate and mitotic arrest of CDK11p110/p58-null mutant mice at the blastocyst stage of embryonic cell development. Mol. Cell. Biol. 24, 3188–3197 (2004)

    Article  CAS  Google Scholar 

  24. Petretti, C. et al. The PITSLRE/CDK11p58 protein kinase promotes centrosome maturation and bipolar spindle formation. EMBO Rep. 7, 418–424 (2006)

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Cornelis, S. et al. Identification and characterization of a novel cell cycle-regulated internal ribosome entry site. Mol. Cell 5, 597–605 (2000)

    Article  CAS  Google Scholar 

  26. Shi, Q. & King, R. W. Chromosome nondisjunction yields tetraploid rather than aneuploid cells in human cell lines. Nature 437, 1038–1042 (2005)

    Article  ADS  CAS  Google Scholar 

  27. Fujiwara, T. et al. Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature 437, 1043–1047 (2005)

    Article  ADS  CAS  Google Scholar 

  28. Brunet, A. et al. 14-3-3 transits to the nucleus and participates in dynamic nucleocytoplasmic transport. J. Cell Biol. 156, 817–828 (2002)

    Article  CAS  Google Scholar 

  29. Wilker, E. W., Grant, R. A., Artim, S. C. & Yaffe, M. B. A structural basis for 14-3-3σ functional specificity. J. Biol. Chem. 280, 18891–18898 (2005)

    Article  CAS  Google Scholar 

  30. Rubinson, D. A. et al. A lentivirus-based system to functionally silence genes in primary mammalian cells, stem cells and transgenic mice by RNA interference. Nature Genet. 33, 401–406 (2003)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank P. Stern, D. Lowery and W. Merrick for reagents and technical assistance. This work was supported by postdoctoral fellowships from the Anna Fuller Fund and the NIH to E.W.W., an EMBO long-term fellowship to M.A.T.M.v.V., the David H. Koch Cancer Research Fund, NIH grants, and a Burroughs-Wellcome Career Development Award to M.B.Y.

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Authors and Affiliations

  1. Department of Biology and, Center for Cancer Research,

    Erik W. Wilker, Marcel A. T. M. van Vugt, Stephen C. Artim, Christian P. Petersen, H. Christian Reinhardt, Yun Feng, Phillip A. Sharp & Michael B. Yaffe

  2. Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA,

    Paul H. Huang, Forest M. White & Michael B. Yaffe

  3. Department of Biochemistry, McGill Cancer Centre, McGill University, Montreal, Quebec, H3G 1Y6, Canada,

    Nahum Sonenberg

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Correspondence to Michael B. Yaffe.

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Wilker, E., van Vugt, M., Artim, S. et al. 14-3-3σ controls mitotic translation to facilitate cytokinesis. Nature 446, 329–332 (2007). https://doi.org/10.1038/nature05584

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