Skip to main content

Advertisement

SpringerLink
Log in

Overexpression and constitutive nuclear localization of cohesin protease Separase protein correlates with high incidence of relapse and reduced overall survival in glioblastoma multiforme

  • Laboratory Investigation
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

An Erratum to this article was published on 06 June 2014

Abstract

Separase, an enzyme that cleaves the chromosomal cohesin during mitosis, is overexpressed in a wide range of human epithelial cancers of breast, bone and prostate (Meyer et al., Clin Cancer Res 15(8):2703–2710, 2009). Overexpression of Separase in animal models results in aneuploidy and tumorigenesis. We have examined the expression and localization of Separase protein in adult and pediatric glioblastoma and normal brain specimens. Immunofluorescence microscopy and Western blot analysis showed significant overexpression of Separase in all adult and a subset of pediatric glioblastoma cells. Tumor status and patient survival strongly correlate with the mislocalization of Separase into the nucleus throughout all stages of the cell cycle. Unlike exclusively nuclear localization in mitotic control cells, glioblastoma samples have a significantly higher number of resting (interphase) cells with strong nuclear Separase staining. Additionally, patient survival analysis demonstrated a strong correlation between overexpression of Separase protein in adult glioblastoma and a high incidence of relapse and reduced overall survival. These results further strengthen our hypothesis that Separase is an oncogene whose overexpression induces tumorigenesis, and indicate that Separase overexpression and aberrant nuclear localization are common in many tumor types and may predict outcome in some human malignancies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Xu H, Tomaszewski JM, McKay MJ (2011) Can corruption of chromosome cohesion create a conduit to cancer? Nat Rev Cancer 11:199–210. doi:10.1038/nrc3018

    Article  CAS  PubMed  Google Scholar 

  2. Solomon DA, Kim T, Diaz-Martinez LA, Fair J, Elkahloun AG, Harris BT, Toretsky JA, Rosenberg SA, Shukla N, Ladanyi M et al (2011) Mutational inactivation of STAG2 causes aneuploidy in human cancer. Science 333:1039–1043. doi:10.1126/science.1203619

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Hagemann C, Weigelin B, Schommer S, Schulze M, Al-Jomah N, Anacker J, Gerngras S, Kuhnel S, Kessler AF, Polat B et al (2011) The cohesin-interacting protein, precocious dissociation of sisters 5A/sister chromatid cohesion protein 112, is up-regulated in human astrocytic tumors. Int J Mol Med 27:39–51. doi:10.3892/ijmm.2010.551

    CAS  PubMed  Google Scholar 

  4. Pati D (2008) Oncogenic activity of separase. Cell Cycle 7:3481–3482

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Kon A, Shih LY, Minamino M, Sanada M, Shiraishi Y, Nagata Y, Yoshida K, Okuno Y, Bando M, Nakato R et al (2013) Recurrent mutations in multiple components of the cohesin complex in myeloid neoplasms. Nat Genet 45:1232–1237. doi:10.1038/ng.2731

    Article  CAS  PubMed  Google Scholar 

  6. Zachariae W, Nasmyth K (1999) Whose end is destruction: cell division and the anaphase-promoting complex. Genes Dev 13:2039–2058

    Article  CAS  PubMed  Google Scholar 

  7. Hauf S, Waizenegger IC, Peters JM (2001) Cohesin cleavage by separase required for anaphase and cytokinesis in human cells. Science 293:1320–1323. doi:10.1126/science.1061376

    Article  CAS  PubMed  Google Scholar 

  8. Haering CH, Nasmyth K (2003) Building and breaking bridges between sister chromatids. BioEssays 25:1178–1191. doi:10.1002/bies.10361

    Article  CAS  PubMed  Google Scholar 

  9. Ciosk R, Zachariae W, Michaelis C, Shevchenko A, Mann M, Nasmyth K (1998) An ESP1/PDS1 complex regulates loss of sister chromatid cohesion at the metaphase to anaphase transition in yeast. Cell 93:1067–1076

    Article  CAS  PubMed  Google Scholar 

  10. Cohen-Fix O, Koshland D (1999) Pds1p of budding yeast has dual roles: inhibition of anaphase initiation and regulation of mitotic exit. Genes Dev 13:1950–1959

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Cohen-Fix O, Peters JM, Kirschner MW, Koshland D (1996) Anaphase initiation in Saccharomyces cerevisiae is controlled by the APC-dependent degradation of the anaphase inhibitor Pds1p. Genes Dev 10:3081–3093

    Article  CAS  PubMed  Google Scholar 

  12. Hornig NC, Knowles PP, McDonald NQ, Uhlmann F (2002) The dual mechanism of separase regulation by securin. Curr Biol 12:973–982

    Article  CAS  PubMed  Google Scholar 

  13. Waizenegger I, Gimenez-Abian JF, Wernic D, Peters JM (2002) Regulation of human separase by securin binding and autocleavage. Curr Biol 12:1368–1378

    Article  CAS  PubMed  Google Scholar 

  14. Stemmann O, Zou H, Gerber SA, Gygi SP, Kirschner MW (2001) Dual inhibition of sister chromatid separation at metaphase. Cell 107:715–726

    Article  CAS  PubMed  Google Scholar 

  15. Huang X, Andreu-Vieyra CV, York JP, Hatcher R, Lu T, Matzuk MM, Zhang P (2008) Inhibitory phosphorylation of separase is essential for genome stability and viability of murine embryonic germ cells. PLoS Biol 6:e15. doi:10.1371/journal.pbio.0060015

    Article  PubMed Central  PubMed  Google Scholar 

  16. Gorr IH, Boos D, Stemmann O (2005) Mutual inhibition of separase and Cdk1 by two-step complex formation. Mol Cell 19:135–141. doi:10.1016/j.molcel.2005.05.022

    Article  CAS  PubMed  Google Scholar 

  17. Meyer R, Fofanov V, Panigrahi A, Merchant F, Zhang N, Pati D (2009) Overexpression and mislocalization of the chromosomal segregation protein separase in multiple human cancers. Clin Cancer Res 15:2703–2710. doi:10.1158/1078-0432.CCR-08-2454

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Zhang N, Ge G, Meyer R, Sethi S, Basu D, Pradhan S, Zhao YJ, Li XN, Cai WW, El-Naggar AK et al (2008) Overexpression of Separase induces aneuploidy and mammary tumorigenesis. Proc Natl Acad Sci USA 105:13033–13038. doi:10.1073/pnas.0801610105

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Mukherjee M, Ge G, Zhang N, Edwards DG, Sumazin P, Sharan SK, Rao PH, Medina D, Pati D (2013) MMTV-Espl1 transgenic mice develop aneuploid, estrogen receptor alpha (ERalpha)-positive mammary adenocarcinomas. Oncogene. doi:10.1038/onc.2013.493

    PubMed Central  Google Scholar 

  20. Allred DC, Harvey JM, Berardo M, Clark GM (1998) Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol 11:155–168

    CAS  PubMed  Google Scholar 

  21. Cancer Genome Atlas Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068. doi:10.1038/nature07385

    Article  Google Scholar 

  22. Madhavan S, Zenklusen JC, Kotliarov Y, Sahni H, Fine HA, Buetow K (2009) Rembrandt: helping personalized medicine become a reality through integrative translational research. Mol Cancer Res 7:157–167. doi:10.1158/1541-7786.MCR-08-0435

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, Gage FH (2002) Functional neurogenesis in the adult hippocampus. Nature 415:1030–1034. doi:10.1038/4151030a

    Article  PubMed  Google Scholar 

  24. Morshead CM, Garcia AD, Sofroniew MV, van Der Kooy D (2003) The ablation of glial fibrillary acidic protein-positive cells from the adult central nervous system results in the loss of forebrain neural stem cells but not retinal stem cells. Eur J Neurosci 18:76–84

    Article  PubMed  Google Scholar 

  25. Nagao K, Adachi Y, Yanagida M (2004) Separase-mediated cleavage of cohesin at interphase is required for DNA repair. Nature 430:1044–1048. doi:10.1038/nature02803

    Article  CAS  PubMed  Google Scholar 

  26. McAleenan A, Clemente-Blanco A, Cordon-Preciado V, Sen N, Esteras M, Jarmuz A, Aragon L (2013) Post-replicative repair involves separase-dependent removal of the kleisin subunit of cohesin. Nature 493:250–254. doi:10.1038/nature11630

    Article  CAS  PubMed  Google Scholar 

  27. Pati D, Haddad BR, Haegele A, Thompson H, Kittrell FS, Shepard A, Montagna C, Zhang N, Ge G, Otta SK et al (2004) Hormone-induced chromosomal instability in p53-null mammary epithelium. Cancer Res 64:5608–5616. doi:10.1158/0008-5472.CAN-03-0629

    Article  CAS  PubMed  Google Scholar 

  28. Milinkovic V, Bankovic J, Rakic M, Milosevic N, Stankovic T, Jokovic M, Milosevic Z, Skender-Gazibara M, Podolski-Renic A, Pesic M et al (2012) Genomic instability and p53 alterations in patients with malignant glioma. Exp Mol Pathol 93:200–206. doi:10.1016/j.yexmp.2012.05.010

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by grants awarded to D. Pati from the National Cancer Institute (1RO1 CA109478 and 1RO1 CA109330).

Conflict of interest

Malini Mukherjee, Tiara Byrd, Vita S. Brawley, Kevin Bielamowicz, Xiao-Nan Li, Fatima Merchant, Saurabh Maitra, Pavel Sumazin, Greg Fuller, Yvonne Kew, David Sun, Suzanne Z. Powell, Nabil M. Ahmed, Nenggang Zhang, and Debananda Pati declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA

    Malini Mukherjee, Tiara Byrd, Vita S. Brawley, Xiao-Nan Li, Pavel Sumazin, Nabil M. Ahmed, Nenggang Zhang & Debananda Pati

  2. Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, 77030, USA

    Tiara Byrd, Vita S. Brawley, Kevin Bielamowicz & Nabil M. Ahmed

  3. Department of Pediatric Hematology/Oncology, Baylor College of Medicine, 1102 Bates St., MC3-3320, Houston, TX, 77030, USA

    Malini Mukherjee, Tiara Byrd, Vita S. Brawley, Kevin Bielamowicz, Xiao-Nan Li, Pavel Sumazin, Nabil M. Ahmed & Debananda Pati

  4. Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA

    Debananda Pati

  5. The Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA

    Xiao-Nan Li, Nabil M. Ahmed, Nenggang Zhang & Debananda Pati

  6. Department of Engineering Technology, University of Houston, 4800 Calhoun Rd., Houston, TX, 77030, USA

    Fatima Merchant

  7. Bauer College of Business, University of Houston, 4800 Calhoun Rd., Houston, TX, 77024, USA

    Saurabh Maitra

  8. Department of Pathology, MD Anderson Cancer Center, Houston, TX, 77030, USA

    Greg Fuller

  9. Methodist Hospital Research Institute, Houston, TX, 77030, USA

    Yvonne Kew, David Sun, Suzanne Z. Powell & Nabil M. Ahmed

Authors
  1. Malini Mukherjee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tiara Byrd
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vita S. Brawley
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kevin Bielamowicz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiao-Nan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fatima Merchant
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Saurabh Maitra
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Pavel Sumazin
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Greg Fuller
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yvonne Kew
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. David Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Suzanne Z. Powell
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Nabil M. Ahmed
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Nenggang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Debananda Pati
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Debananda Pati.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 59 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mukherjee, M., Byrd, T., Brawley, V.S. et al. Overexpression and constitutive nuclear localization of cohesin protease Separase protein correlates with high incidence of relapse and reduced overall survival in glioblastoma multiforme. J Neurooncol 119, 27–35 (2014). https://doi.org/10.1007/s11060-014-1458-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-014-1458-6

Keywords

Search

Navigation