Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

CtBPs promote mitotic fidelity through their activities in the cell nucleus

Abstract

CtBPs form NADH-sensitive chromatin-modifying complexes, which link cellular metabolism to gene transcription. They also function in the cytoplasm to regulate Golgi fissioning; their inhibition can consequently cause a Golgi-dependent checkpoint in G2. We have recently identified a novel role of CtBPs in the maintenance of mitotic fidelity; inhibition of CtBP synthesis resulting in reduced association of aurora B with mitotic chromatin and aberrant segregation of chromosomes. Here, we demonstrate that it is the interaction of CtBPs with transcriptional regulators and/or chromatin-modifying enzymes in the cell nucleus, rather than their role in Golgi fission, which is critical for the maintenance of mitotic fidelity.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  • Bergman LM, Birts CN, Darley M, Gabrielli B, Blaydes JP . (2009). CtBPs promote cell survival through the maintenance of mitotic fidelity. Mol Cell Biol 29: 4539–4551.

    Article  CAS  Google Scholar 

  • Bergman LM, Blaydes JP . (2006). C-terminal binding proteins: Emerging roles in cell survival and tumorigenesis. Apoptosis 11: 879–888.

    Article  CAS  Google Scholar 

  • Bergman LM, Morris L, Darley M, Mirnezami AH, Gunatilake SC, Blaydes JP . (2006). Role of the unique N-terminal domain of CtBP2 in determining the subcellular localisation of CtBP family proteins. BMC Cell Biol 7: 35.

    Article  Google Scholar 

  • Blaydes JP, Gire V, Rowson J, Wynford-Thomas D . (1997). Tolerance of high levels of wild-type p53 in transformed epithelial cells dependent on auto-regulation by mdm-2. Oncogene 14: 1859–1868.

    Article  CAS  Google Scholar 

  • Boyd JM, Subramanian T, Schaeper U, La Regina M, Bayley S, Chinnadurai G . (1993). A region in the C-terminus of adenovirus 2/5 E1a protein is required for association with a cellular phosphoprotein and important for the negative modulation of T24-ras mediated transformation, tumorigenesis and metastasis. Embo J 12: 469–478.

    Article  CAS  Google Scholar 

  • Chen YW, Paliwal S, Draheim K, Grossman SR, Lewis BC . (2008). p19Arf inhibits the invasion of hepatocellular carcinoma cells by binding to C-terminal binding protein. Cancer Res 68: 476–482.

    Article  CAS  Google Scholar 

  • Cheok CF, Kua N, Kaldis P, Lane DP . (2010). Combination of nutlin-3 and VX-680 selectively targets p53 mutant cells with reversible effects on cells expressing wild-type p53. Cell Death Differ 17: 1486–14500.

    Article  CAS  Google Scholar 

  • Chinnadurai G . (2007). Transcriptional regulation by C-terminal binding proteins. Int J Biochem Cell Biol 39: 1593–1607.

    Article  CAS  Google Scholar 

  • Chinnadurai G . (2009). The transcriptional corepressor CtBP: a foe of multiple tumor suppressors. Cancer Res 69: 731–734.

    Article  CAS  Google Scholar 

  • Colanzi A, Carcedo CH, Persico A, Cericola C, Turacchio G, Bonazzi M et al. (2007). The Golgi mitotic checkpoint is controlled by BARS-dependent fission of the Golgi ribbon into separate stacks in G2. EMBO J 26: 2465–2476.

    Article  CAS  Google Scholar 

  • Ditchfield C, Keen N, Taylor SS . (2005). The Ipl1/Aurora kinase family: methods of inhibition and functional analysis in mammalian cells. Methods Mol Biol 296: 371–381.

    CAS  PubMed  Google Scholar 

  • Eot-Houllier G, Fulcrand G, Magnaghi-Jaulin L, Jaulin C . (2009). Histone deacetylase inhibitors and genomic instability. Cancer Lett 274: 169–176.

    Article  CAS  Google Scholar 

  • Grooteclaes M, Deveraux Q, Hildebrand J, Zhang Q, Goodman RH, Frisch SM . (2003). C-terminal-binding protein corepresses epithelial and proapoptotic gene expression programs. Proc Natl Acad Sci USA 100: 4568–4573.

    Article  CAS  Google Scholar 

  • Hidalgo Carcedo C, Bonazzi M, Spano S, Turacchio G, Colanzi A, Luini A et al. (2004). Mitotic Golgi partitioning is driven by the membrane-fissioning protein CtBP3/BARS. Science 305: 93–96.

    Article  Google Scholar 

  • Kovi RC, Paliwal S, Pande S, Grossman SR . (2010). An ARF/CtBP2 complex regulates BH3-only gene expression and p53-independent apoptosis. Cell Death Differ 17: 513–521.

    Article  CAS  Google Scholar 

  • Kuppuswamy M, Vijayalingam S, Zhao LJ, Zhou Y, Subramanian T, Ryerse J et al. (2008). Role of the PLDLS-binding cleft region of CtBP1 in recruitment of core and auxiliary components of the corepressor complex. Mol Cell Biol 28: 269–281.

    Article  CAS  Google Scholar 

  • Mirnezami AH, Campbell SJ, Darley M, Primrose JN, Johnson PWM, Blaydes JP . (2003). Hdm2 recruits a hypoxia sensitive co-repressor to negatively regulate p53-dependent transcription. Curr Biol 13: 1234–1239.

    Article  CAS  Google Scholar 

  • Mroz EA, Baird AH, Michaud WA, Rocco JW . (2008). COOH-terminal binding protein regulates expression of the p16INK4A tumor suppressor and senescence in primary human cells. Cancer Res 68: 6049–6053.

    Article  CAS  Google Scholar 

  • Nardini M, Spano S, Cericola C, Pesce A, Massaro A, Millo E et al. (2003). CtBP/BARS: a dual-function protein involved in transcription co-repression and Golgi membrane fission. Embo J 22: 3122–3130.

    Article  CAS  Google Scholar 

  • Paliwal S, Pande S, Kovi RC, Sharpless NE, Bardeesy N, Grossman SR . (2006). Targeting of C-terminal binding protein (CtBP) by ARF results in p53-independent apoptosis. Mol Cell Biol 26: 2360–2372.

    Article  CAS  Google Scholar 

  • Phelps RA, Chidester S, Dehghanizadeh S, Phelps J, Sandoval IT, Rai K et al. (2009). A two-step model for colon adenoma initiation and progression caused by APC loss. Cell 137: 623–634.

    Article  CAS  Google Scholar 

  • Quinlan KGR, Verger A, Kwok A, Lee SHY, Perdomo J, Nardini M et al. (2006). Role of the C-terminal binding protein PXDLS motif binding cleft in protein interactions and transcriptional repression. Molecular and Cellular Biology 26: 8202–8213.

    Article  CAS  Google Scholar 

  • Schaeper U, Boyd JM, Verma S, Uhlmann E, Subramanian T, Chinnadurai G . (1995). Molecular cloning and characterization of a cellular phosphoprotein that interacts with a conserved C-terminal domain of adenovirus E1A involved in negative modulation of oncogenic transformation. Proc Natl Acad Sci USA 92: 10467–10471.

    Article  CAS  Google Scholar 

  • Shi Y, Sawada J, Sui G, Affar el B, Whetstine JR, Lan F et al. (2003). Coordinated histone modifications mediated by a CtBP co-repressor complex. Nature 422: 735–738.

    Article  CAS  Google Scholar 

  • Stevens FE, Beamish H, Warrener R, Gabrielli B . (2008). Histone deacetylase inhibitors induce mitotic slippage. Oncogene 27: 1345–1354.

    Article  CAS  Google Scholar 

  • Warrener R, Beamish H, Burgess A, Waterhouse NJ, Giles N, Fairlie D et al. (2003). Tumor cell-selective cytotoxicity by targeting cell cycle checkpoints. FASEB J 17: 1550–1552.

    Article  CAS  Google Scholar 

  • Yang JS, Gad H, Lee SY, Mironov A, Zhang L, Beznoussenko GV et al. (2008). A role for phosphatidic acid in COPI vesicle fission yields insights into Golgi maintenance. Nat Cell Biol 10: 1146–1153.

    Article  CAS  Google Scholar 

  • Zhang Q, Piston DW, Goodman RH . (2002). Regulation of corepressor function by nuclear NADH. Science 295: 1895–1897.

    CAS  PubMed  Google Scholar 

  • Zhang Q, Yoshimatsu Y, Hildebrand J, Frisch SM, Goodman RH . (2003). Homeodomain interacting protein kinase 2 promotes apoptosis by downregulating the transcriptional corepressor CtBP. Cell 115: 177–186.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to Matthew Darley for the generation of plasmid reagents, Patrick Duriez for the preparation of GST fusion proteins for microinjection, and the Southampton School of Medicine Bioimaging Unit for assistance with live cell imaging. Funding for the work was from the UK Breast Cancer Campaign.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to J P Blaydes.

Ethics declarations

Competing interests

The authors declare no conflict of interest

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Birts, C., Bergman, L. & Blaydes, J. CtBPs promote mitotic fidelity through their activities in the cell nucleus. Oncogene 30, 1272–1280 (2011). https://doi.org/10.1038/onc.2010.507

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2010.507

Keywords

This article is cited by

Search

Quick links