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Survivin splice variants regulate the balance between proliferation and cell death

Oncogene volume 24, pages 1994–2007 (2005)Cite this article

Abstract

Survivin is an inhibitor of apoptosis protein that also plays critical roles in regulating the cell cycle and mitosis. Its prominent expression in essentially all human malignancies, and low or absent expression in most normal tissues, suggests that it would be an ideal target for cancer-directed therapy. Impeding development of safe and effective survivin antagonists for clinical use is a lack of understanding of the molecular mechanisms by which survivin differentially affects apoptosis and cell division, in normal and malignant cells. We show that the diverse functional roles of survivin can be explained, in part, by its heterodimerization with survivin splice variants in tumor cells. Survivin and survivin-ΔEx3 interact within the mitochondria where they may inhibit mitochondrial-dependent apoptosis. If the expression of all survivin forms is eliminated by siRNA transfections, cells undergo both apoptosis and defective cell division. Overall, we provide new insights suggesting that targeting specific survivin isoforms, rather than survivin alone, may selectively and effectively destroy tumor cells. These findings are likely to have a significant impact in the design of biologic agents for clinical therapy.

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Abbreviations

MEF:

mouse embryo fibroblast

GFP:

green fluorescent protein

IAP:

inhibitor of apoptosis

BIR:

baculovirus inhibition of apoptosis protein repeat

siRNA:

small interfering RNA

PCD:

programmed cell death

VCR:

vincristine

References

  • Altieri DC . (2003). Oncogene, 22, 8581–8589.

  • Altura RA, Olshefski RS, Jiang Y and Boue DR . (2003). Br. J. Cancer, 89, 1743–1749.

  • Altznauer F, Martinelli S, Yousefi S, Thurig C, Schmid I, Conway EM, Schoni MH, Vogt P, Mueller C, Fey MF, Zangemeister-Wittke U and Simon HU . (2004). J. Exp. Med., 199, 1343–1354.

  • Ambrosini G, Adida C and Altieri DC . (1997). Nat. Med., 3, 917–921.

  • Armit CJ, O'Dea S, Clarke AR and Harrison DJ . (2002). BMC Cell Biol., 3, 27.

  • Badran A, Yoshida A, Ishikawa K, Goi T, Yamaguchi A, Ueda T and Inuzuka M . (2004). Biochem. Biophys. Res. Commun., 314, 902–907.

  • Bronfman M, Loyola G and Koenig CS . (1998). Anal. Biochem., 255, 252–256.

  • Brummelkamp TR, Bernards R and Agami R . (2002). Science, 296, 550–553.

  • Chakravarti A, Noll E, Black PM, Finkelstein DF, Finkelstein DM, Dyson NJ and Loeffler JS . (2002). J. Clin. Oncol., 20, 1063–1068.

  • Chen J, Jin S, Tahir SK, Zhang H, Liu X, Sarthy AV, McGonigal TP, Liu Z, Rosenberg SH and Ng SC . (2003). J. Biol. Chem., 278, 486–490.

  • Chen J, Wu W, Tahir SK, Kroeger PE, Rosenberg SH, Cowsert LM, Bennett F, Krajewski S, Krajewska M, Welsh K, Reed JC and Ng SC . (2000). Neoplasia., 2, 235–241.

  • Conway EM, Pollefeyt S, Cornelissen J, DeBaere I, Steiner-Mosonyi M, Ong K, Baens M, Collen D and Schuh AC . (2000). Blood, 95, 1435–1442.

  • Conway EM, Pollefeyt S, Steiner-Mosonyi M, Luo W, Devriese A, Lupu F, Bono F, Leducq N, Dol F, Schaeffer P, Collen D and Herbert JM . (2002). Gastroenterology, 123, 619–631.

  • Conway EM, Zwerts F, Van Eygen V, DeVriese A, Nagai N, Luo W and Collen D . (2003). Am. J. Pathol., 163, 935–946.

  • Dohi T, Beltrami E, Wall NR, Plescia J and Altieri DC . (2004). J. Clin. Invest., 114, 1117–1127.

  • Emanuelsson O, Nielsen H, Brunak S and von Heijne G . (2000). J. Mol. Biol., 300, 1005–1016.

  • Fukuda S, Foster RG, Porter SB and Pelus LM . (2002). Blood, 100, 2463–2471.

  • Green DR and Reed JC . (1998). Science, 281, 1309–1312.

  • Horton P and Nakai K . (1997). Proc. Int. Conf. Intell. Syst. Mol. Biol., 5, 147–152.

  • Islam A, Kageyama H, Hashizume K, Kaneko Y and Nakagawara A . (2000a). Med. Pediatr. Oncol., 35, 550–553.

  • Islam A, Kageyama H, Takada N, Kawamoto T, Takayasu H, Isogai E, Ohira M, Hashizume K, Kobayashi H, Kaneko Y and Nakagawara A . (2000b). Oncogene, 19, 617–623.

  • Jacobsen PF, Jenkyn DJ and Papadimitriou JM . (1985). J. Neuropathol. Exp. Neurol., 44, 472–485.

  • Johnston JA, Ward CL and Kopito RR . (1998). J. Cell. Biol., 143, 1883–1898.

  • Jurgensmeier JM, Xie Z, Deveraux Q, Ellerby L, Bredesen D and Reed JC . (1998). Proc. Natl. Acad. Sci. USA, 95, 4997–5002.

  • Kluck RM, Esposti MD, Perkins G, Renken C, Kuwana T, Bossy-Wetzel E, Goldberg M, Allen T, Barber MJ, Green DR and Newmeyer DD . (1999). J. Cell Biol., 147, 809–822.

  • Kobayashi K, Hatano M, Otaki M, Ogasawara T and Tokuhisa T . (1999). Proc. Natl. Acad. Sci. USA, 96, 1457–1462.

  • Krieg A, Mahotka C, Krieg T, Grabsch H, Muller W, Takeno S, Suschek CV, Heydthausen M, Gabbert HE and Gerharz CD . (2002). Br. J. Cancer, 86, 737–743.

  • LaCasse EC, Baird S, Korneluk RG and MacKenzie AE . (1998). Oncogene, 17, 3247–3259.

  • Lee SH, Kang HS, Rhee CH, Kim MS, Kwon HC, Park MJ, Park IC, Lee CT, Kim CM and Hong SI . (2001). Childs Nerv. Syst., 17, 134–138.

  • Li F, Ackermann EJ, Bennett CF, Rothermel AL, Plescia J, Tognin S, Villa A, Marchisio PC and Altieri DC . (1999). Nat. Cell Biol., 1, 461–466.

  • Li F and Altieri DC . (1999). Biochem. J., 344 (Part 2), 305–311.

  • Mahotka C, Krieg T, Krieg A, Wenzel M, Suschek CV, Heydthausen M, Gabbert HE and Gerharz CD . (2002a). Int. J. Cancer, 100, 30–36.

  • Mahotka C, Liebmann J, Wenzel M, Suschek CV, Schmitt M, Gabbert HE and Gerharz CD . (2002b). Cell. Death Differ., 9, 1334–1342.

  • Mahotka C, Wenzel M, Springer E, Gabbert HE and Gerharz CD . (1999). Cancer Res., 59, 6097–6102.

  • Margolis RL, Lohez OD and Andreassen PR . (2003). J. Cell. Biochem., 88, 673–683.

  • Meraldi P, Honda R and Nigg EA . (2002). EMBO J., 21, 483–492.

  • Mundt KE, Golsteyn RM, Lane HA and Nigg EA . (1997). Biochem. Biophys. Res. Commun., 239, 377–385.

  • Nielsen H, Engelbrecht J, Brunak S and von Heijne G . (1997). Protein Eng., 10, 1–6.

  • Pennartz S, Belvindrah R, Tomiuk S, Zimmer C, Hofmann K, Conradt M, Bosio A and Cremer H . (2004). Mol. Cell Neurosci., 25, 692–706.

  • Song Z, Yao X and Wu M . (2003). J. Biol. Chem., 278, 23130–23140.

  • Terada Y, Tatsuka M, Suzuki F, Yasuda Y, Fujita S and Otsu M . (1998). EMBO J., 17, 667–676.

  • U HS, Banaie A, Rigby L and Chen J . (1998). Neurosci. Lett., 244, 41–46.

  • Uren AG, Wong L, Pakusch M, Fowler KJ, Burrows FJ, Vaux DL and Choo KH . (2000). Curr. Biol., 10, 1319–1328.

  • Verdecia MA, Huang H, Dutil E, Kaiser DA, Hunter T and Noel JP . (2000). Nat. Struct. Biol., 7, 602–608.

  • Verhagen AM, Coulson EJ and Vaux DL . (2001). Genome Biol., 2, REVIEWS3009.

  • Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, Moritz RL, Simpson RJ and Vaux DL . (2000). Cell, 102, 43–53.

  • Wang HW, Sharp TV, Koumi A, Koentges G and Boshoff C . (2002). EMBO J., 21, 2602–2615.

  • Wheatley SP, Carvalho A, Vagnarelli P and Earnshaw WC . (2001). Curr. Biol., 11, 886–890.

  • Yamada Y, Kuroiwa T, Nakagawa T, Kajimoto Y, Dohi T, Azuma H, Tsuji M, Kami K and Miyatake S . (2003). J. Neurosurg., 99, 738–745.

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Acknowledgements

This work was supported by the Elsa U. Pardee Foundation and the Hope Street Kids Foundation. We thank Tara Grove and Lynette Rogers for their technical assistance. We also thank John Gilbert for his editorial assistance with this manuscript.

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Authors and Affiliations

  1. Center for Childhood Cancer, Columbus Children's Research Institute, The Ohio State University, Columbus, OH, USA

    Hugo Caldas, Yuying Jiang, Michael P Holloway, Jason Fangusaro & Rachel A Altura

  2. Department of Pediatrics, The Ohio State University, Columbus, OH, USA

    Jason Fangusaro & Rachel A Altura

  3. Institute of Pathology, Heinrich Heine University, Düsseldorf, Germany

    Csaba Mahotka

  4. The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, University of Leuven, Leuven, Belgium

    Edward M Conway

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  1. Hugo Caldas
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  2. Yuying Jiang
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Correspondence to Rachel A Altura.

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Caldas, H., Jiang, Y., Holloway, M. et al. Survivin splice variants regulate the balance between proliferation and cell death. Oncogene 24, 1994–2007 (2005). https://doi.org/10.1038/sj.onc.1208350

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