Molecular Biology

, Volume 52, Issue 3, pp 436–445 | Cite as

The Novel Short Isoform of Securin Stimulates the Expression of Cyclin D3 and Angiogenesis Factors VEGFA and FGF2, but Does Not Affect the Expression of MYC Transcription Factor

  • D. E. Demin
  • A. V. Bogolyubova
  • D. V. Zlenko
  • A. N. Uvarova
  • A. V. Deikin
  • L. V. Putlyaeva
  • P. V. Belousov
  • N. A. Mitkin
  • K. V. Korneev
  • E. N. Sviryaeva
  • I. V. Kulakovskiy
  • K. A. Tatosyan
  • D. V. Kuprash
  • A. M. Schwartz
Molecular Cell Biology


Pituitary tumor-transforming gene-1 (PTTG1) encodes securin, a multifunctional protein involved in development of various types of cancer. Securin participates in the regulation of sister chromatids separation and the expression of multiple genes involved in the control of the cell cycle, metabolism, and angiogenesis. In several human cell lines, we have found a novel short isoform of securin mRNA, which does not contain exons 3 and 4. After the translation of this new mRNA, a shortened protein is produced that, like the full-size form, is able to activate the transcription of cyclin D3 gene (CCND3), which controls the G1/S transition and angiogenesis factors VEGFA (vascular endothelial growth factor), and FGF2 (fibroblast growth factor 2) in HEK293 cells. However, unlike the full-size protein, the short isoform of PTTG1 does not affect the MYC gene expression because it lacks the DNA-binding domain, which is needed for its interactions with the MYC promoter. Furthermore, the short form of securin does not influence the expression of MYC transcriptional targets, such as TP53 and IL-8. Thus, we found a novel isoform of securin which is able to activate a more restricted repertoire of genes compared to the full-size protein.


PTTG1 securin alternative splicing cyclin D3 FGF2 VEGF transcription regulation 



pituitary tumor-transforming gene-1


cyclin D3


vascular endothelial growth factor


fibroblast growth factor 2




anaphase promoting complex


specificity protein 1


PTTG1-binding factor


upstream stimulatory factor 1. IPTG, isopropyl-β-D-1-thiogalactopyranoside, аa, amino acid residue


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Pei L., Melmed S. 1997. Isolation and characterization of a pituitary tumor-transforming gene (PTTG). Mol. Endocrinol. 11, 433–441.CrossRefPubMedGoogle Scholar
  2. 2.
    Zhang X., Horwitz G.A., Heaney A.P., et al. 1999. Pituitary tumor transforming gene (PTTG) expression in pituitary adenomas. J. Clin. Endocrinol. Metabolism. 84, 761–767.CrossRefGoogle Scholar
  3. 3.
    Heaney A.P., Singson R., McCabe C.J., et al. 2000. Expression of pituitary-tumour transforming gene in colorectal tumours. Lancet. 355, 716–719.CrossRefPubMedGoogle Scholar
  4. 4.
    Heaney A.P., Nelson V., Fernando M., Horwitz G. 2001. Transforming events in thyroid tumorigenesis and their association with follicular lesions. J. Clin. Endocrinol. Metabolism. 86, 5025–5032.CrossRefGoogle Scholar
  5. 5.
    Solbach C., Roller M., Fellbaum C., et al. 2004. PTTG mRNA expression in primary breast cancer: a prognostic marker for lymph node invasion and tumor recurrence. Breast. 13, 80–81.CrossRefPubMedGoogle Scholar
  6. 6.
    Tsai S.J., Lin S.J., Cheng Y.M., et al. 2005. Expression and functional analysis of pituitary tumor transforming gene-1 [corrected] in uterine leiomyomas. J. Clin. Endocrinol. Metabolism. 90, 3715–3723.CrossRefGoogle Scholar
  7. 7.
    Wondergem B., Zhang Z., Huang D., et al. 2012. Expression of the PTTG1 oncogene is associated with aggressive clear cell renal cell carcinoma. Cancer Res. 72, 4361–4371.CrossRefPubMedGoogle Scholar
  8. 8.
    Hamid T., Malik M.T., Kakar S.S. 2005. Ectopic expression of PTTG1/securin promotes tumorigenesis in human embryonic kidney cells. Mol. Cancer. 4, 3.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Cho-Rok J., Yoo J., Jang Y.J., et al. 2006. Adenovirusmediated transfer of siRNA against PTTG1 inhibits liver cancer cell growth in vitro and in vivo. Hepatology. 43, 1042–1052.CrossRefPubMedGoogle Scholar
  10. 10.
    Waizenegger I., Gimenez-Abian J.F., Wernic D., Peters J.M. 2002. Regulation of human separase by securin binding and autocleavage. Curr. Biol. 12 (16), 1368–1378.CrossRefPubMedGoogle Scholar
  11. 11.
    Zou H., McGarry T.J., Bernal T., Kirschner M.W. 1999. Identification of a vertebrate sister-chromatid separation inhibitor involved in transformation and tumorigenesis. Science. 285, 418–422.CrossRefPubMedGoogle Scholar
  12. 12.
    Jin L., Williamson A., Banerjee S., Philipp I., Rape M. 2008. Mechanism of ubiquitin-chain formation by the human anaphase-promoting complex. Cell. 133, 653–665.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Pfleger C.M., Kirschner M.W. 2000. The KEN box: An APC recognition signal distinct from the D box targeted by Cdh1. Genes Dev. 14, 655–665.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Ly T., Ahmad Y., Shlien A., et al. 2014. A proteomic chronology of gene expression through the cell cycle in human myeloid leukemia cells. eLife. 3, e01630.CrossRefGoogle Scholar
  15. 15.
    Tong Y., Tan Y., Zhou C., Melmed S. 2007. Pituitary tumor transforming gene interacts with Sp1 to modulate G1/S cell phase transition. Oncogene. 26, 5596–5605.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Pei L. 2001. Identification of c-myc as a down-stream target for pituitary tumor-transforming gene. J. Biol. C. 276, 8484–8491.CrossRefGoogle Scholar
  17. 17.
    Hamid T., Kakar S.S. 2004. PTTG/securin activates expression of p53 and modulates its function. Mol. Cancer. 3, 18.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Horwitz G.A., Miklovsky I., Heaney A.P., R et al. 2003. Human pituitary tumor-transforming gene (PTTG1) motif suppresses prolactin expression. Mol. Endocrinol. 17, 600–609.CrossRefPubMedGoogle Scholar
  19. 19.
    Pore N., Liu S., Shu H.K., et al. 2004. Sp1 is involved in Akt-mediated induction of VEGF expression through an HIF-1-independent mechanism. Mol. Biol. Cell. 15, 4841–4853.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Chien W., Pei L. 2000. A novel binding factor facilitates nuclear translocation and transcriptional activation function of the pituitary tumor-transforming gene product. J. Biol. Chem. 275, 19422–19427.CrossRefPubMedGoogle Scholar
  21. 21.
    Bernal J.A., Luna R., Espina A., et al. 2002. Human securin interacts with p53 and modulates p53-mediated transcriptional activity and apoptosis. Nat. Genet. 32, 306–311.CrossRefPubMedGoogle Scholar
  22. 22.
    Karpova M.B., Schoumans J., Ernberg I., et al. 2005. Raji revisited: Cytogenetics of the original Burkitt’s lymphoma cell line. Leukemia. 19, 159–161.CrossRefPubMedGoogle Scholar
  23. 23.
    Schneider U., Schwenk H.U., Bornkamm G. 1977. Characterization of EBV-genome negative “null” and “T” cell lines derived from children with acute lymphoblastic leukemia and leukemic transformed non-Hodgkin lymphoma. Int. J. Cancer. 19, 621–626.CrossRefPubMedGoogle Scholar
  24. 24.
    Lemoine N.R., Mayall E.S., Jones T., et al. 1989. Characterisation of human thyroid epithelial cells immortalised in vitro by simian virus 40 DNA transfection. Br. J. Cancer. 60, 897–903.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Lozzio C.B., Lozzio B.B. 1975. Human chronic myelogenous leukemia cell-line with positive Philadelphia chromosome. Blood. 45, 321–334.PubMedGoogle Scholar
  26. 26.
    Boyd D., Florent G., Kim P., Brattain M. 1988. Determination of the levels of urokinase and its receptor in human colon carcinoma cell lines. Cancer Res. 48, 3112–3116.PubMedGoogle Scholar
  27. 27.
    Knowles B.B., Howe C.C., Aden D.P. 1980. Human hepatocellular carcinoma cell lines secrete the major plasma proteins and hepatitis B surface antigen. Science. 209, 497–499.CrossRefPubMedGoogle Scholar
  28. 28.
    Sugarman B.J., Aggarwal B.B., Hass P.E., et al. 1985. Recombinant human tumor necrosis factor-alpha: Effects on proliferation of normal and transformed cells in vitro. Science. 230, 943–945.CrossRefPubMedGoogle Scholar
  29. 29.
    Shaw G., Morse S., Ararat M., Graham F.L. 2002. Preferential transformation of human neuronal cells by human adenoviruses and the origin of HEK 293 cells. FASEB J. 16, 869–871.CrossRefPubMedGoogle Scholar
  30. 30.
    Savvateeva L.V., Schwartz A.M., Gorshkova L.B., et al. 2015. Prophylactic admission of an in vitro reconstructed complexes of human recombinant heat shock proteins and melanoma antigenic peptides activates anti-melanoma responses in mice. Curr. Mol. Med. 15, 462–468.CrossRefPubMedGoogle Scholar
  31. 31.
    Afanasyeva M.A., Britanova L.V., Korneev K.V., et al. 2014. Clusterin is a potential lymphotoxin beta receptor target that is upregulated and accumulates in germinal centers of mouse spleen during immune response. PLoS One. 9, e98349.CrossRefGoogle Scholar
  32. 32.
    Schwartz A.M., Putlyaeva L.V., Covich M., et al. 2016. Early B-cell factor 1 (EBF1) is critical for transcriptional control of SLAMF1 gene in human B cells. Biochim. Biophys. Acta. 1859, 1259–1268.CrossRefPubMedGoogle Scholar
  33. 33.
    Mitkin N.A., Hook C.D., Schwartz A.M., et al. 2015. p53-dependent expression of CXCR5 chemokine receptor in MCF-7 breast cancer cells. Sci. Rep. 5, 9330.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Harrow J., Frankish A., Gonzalez J.M., et al. 2012. GENCODE: The reference human genome annotation for The ENCODE Project. Genome Res. 22, 1760–1774.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Yates A., Akanni W., Amode M.R., et al. 2016. Ensembl 2016. Nucleic Acids Res. 44, D710–D716.CrossRefPubMedGoogle Scholar
  36. 36.
    Pervouchine D.D., Knowles D.G., Guigo R. 2013. Intron-centric estimation of alternative splicing from RNA-seq data. Bioinformatics. 29, 273–274.CrossRefPubMedGoogle Scholar
  37. 37.
    Mele M., Ferreira P.G., Reverter F., et al. 2015. Human genomics. The human transcriptome across tissues and individuals. Science. 348, 660–665.PubMedGoogle Scholar
  38. 38.
    Sanchez-Puig N., Veprintsev D.B., Fersht A.R. 2005. Human full-length securin is a natively unfolded protein. Protein Sci. 14, 1410–1418.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Xu D., Zhang Y. 2012. Ab initio protein structure assembly using continuous structure fragments and optimized knowledge-based force field. Proteins. 80, 1715–1735.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Boelaert K., Smith V.E., Stratford A.L., et al. 2007. PTTG and PBF repress the human sodium iodide symporter. Oncogene. 26, 4344–4356.CrossRefPubMedGoogle Scholar
  41. 41.
    el-Deiry W.S., Tokino T., Velculescu V.E., et al. 1993. WAF1, a potential mediator of p53 tumor suppression. Cell. 75, 817–825.CrossRefPubMedGoogle Scholar
  42. 42.
    Fanning W.J., Thomas C.S., Jr., Roach A., et al. 1991. Prophylaxis of atrial fibrillation with magnesium sulfate after coronary artery bypass grafting. Ann. Thoracic Surgery. 52, 529–533.CrossRefGoogle Scholar
  43. 43.
    Barbosa-Morais N.L., Irimia M., Pan Q., et al. 2012. The evolutionary landscape of alternative splicing in vertebrate species. Science. 338, 1587–1583.CrossRefPubMedGoogle Scholar
  44. 44.
    Wang E.T., Sandberg R., Luo S., et al. 2008. Alternative isoform regulation in human tissue transcriptomes. Nature. 456, 470–476.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Oaks M.K., Hallett K.M., Penwell R.T., et al. 2000. A native soluble form of CTLA-4. Cell. Immunol. 201, 144–153.CrossRefPubMedGoogle Scholar
  46. 46.
    Tazi J., Bakkour N., Stamm S. 2009. Alternative splicing and disease. Biochim. Biophys. Acta. 1792, 14–26.CrossRefPubMedGoogle Scholar
  47. 47.
    da Costa P.J., Menezes J., Romao L. 2017. The role of alternative splicing coupled to nonsense-mediated mRNA decay in human disease. Int. J. Biochem. Cell Biol. (in press).Google Scholar
  48. 48.
    Ueda H., Howson J.M., Esposito L., et al. 2003. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature. 423, 506–511.CrossRefPubMedGoogle Scholar
  49. 49.
    Heggarty S., Suppiah V., Silversides J., et al. 2007. CTLA4 gene polymorphisms and multiple sclerosis in Northern Ireland. J. Neuroimmunol. 187, 187–191.CrossRefPubMedGoogle Scholar
  50. 50.
    Wang Z., Liu T. 2017. Placental growth factor signaling regulates isoform splicing of vascular endothelial growth factor A in the control of lung cancer cell metastasis. Mol. Cell. Biochem. (in press).Google Scholar
  51. 51.
    Liu B., Hong S., Tang Z., Yu H., Giam C.Z. 2005. HTLV-I Tax directly binds the Cdc20-associated anaphase-promoting complex and activates it ahead of schedule. Proc. Natl Acad. Sci. U. S. A. 102, 63–68.CrossRefPubMedGoogle Scholar

Copyright information

© Pleiades Publishing, Inc. 2018

Authors and Affiliations

  • D. E. Demin
    • 1
    • 2
  • A. V. Bogolyubova
    • 1
    • 3
  • D. V. Zlenko
    • 3
  • A. N. Uvarova
    • 1
    • 3
  • A. V. Deikin
    • 4
  • L. V. Putlyaeva
    • 1
  • P. V. Belousov
    • 1
  • N. A. Mitkin
    • 1
  • K. V. Korneev
    • 1
    • 3
  • E. N. Sviryaeva
    • 1
  • I. V. Kulakovskiy
    • 1
    • 5
  • K. A. Tatosyan
    • 1
  • D. V. Kuprash
    • 1
    • 2
    • 3
  • A. M. Schwartz
    • 1
    • 2
  1. 1.Engelhardt Institute of Molecular BiologyRussian Academy of SciencesMoscowRussia
  2. 2.Moscow Institute of Physics and TechnologyDolgoprydnyRussia
  3. 3.Faculty of BiologyMoscow State UniversityMoscowRussia
  4. 4.Institute of Gene BiologyRussian Academy of SciencesMoscowRussia
  5. 5.Vavilov Institute of General GeneticsRussian Academy of SciencesMoscowRussia

Personalised recommendations