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The Oncofetal Gene Survivin Promotes Cell Proliferation and Survival in Primary Human Osteoblastic Cells

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Abstract

Survivin, the smallest member of the inhibitor of apoptosis gene family, is critical for the regulation of mitosis and maintenance of cell viability during embryonic development and cancer, while not being detectable in most adult differentiated tissues. We know little about whether survivin plays any physiological or pathophysiological role in the adult musculoskeletal system. We studied the expression of survivin in primary human osteoblastic cells and its biological functions in vitro. Survivin was detected by immunoblotting and real-time PCR. Subcellular localization was analyzed by immunofluorescence. Transfection of siRNA and plasmids coding for wild-type survivin was performed to study survivin function, i.e., proliferation and apoptosis assays. Survivin mRNA and protein are expressed in primary human osteoblastic cells. During interphase survivin localizes predominantly to the cytoplasmic compartment, which is relevant for the organization of the spindle apparatus during mitosis. Survivin knockdown resulted in an arrest of the cell cycle at the G2/M phase and increased rates of apoptosis. Elevated levels of survivin in primary human osteoblasts enhanced proliferation and cell viability. Taken together, we demonstrate for the first time that survivin is expressed in primary human osteoblastic cells on the mRNA and protein levels. Our results indicate that survivin is a critical factor for cell division and cell viability in primary human osteoblastic cells. Learning more about survivin’s role in human osteoblasts could be an important step toward understanding the complex processes involved in bone homeostasis and remodeling.

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References

  1. Boyce BF, Xing L, Jilka RJ et al (2002) Apoptosis in bone cells. In: Bilezikian JP, Raisz LG, Rodan GA (eds) Principles of bone biology, 2nd edn. Academic Press, London, pp 151–168

    Chapter  Google Scholar 

  2. Raaijmakers MH, Mukherjee S, Guo S et al (2010) Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. Nature 464:852–857

    Article  PubMed  CAS  Google Scholar 

  3. Mansukhani A, Bellosta P, Sahni M, Basilico C (2000) Signaling by fibroblast growth factors (FGF) and fibroblast growth factor receptor 2 (FGFR2)-activating mutations blocks mineralization and induces apoptosis in osteoblasts. J Cell Biol 149:1297–1308

    Article  PubMed  CAS  Google Scholar 

  4. Adida C, Crotty PL, McGrath J et al (1998) Developmentally regulated expression of the novel cancer anti-apoptosis gene survivin in human and mouse differentiation. Am J Pathol 152:43–49

    PubMed  CAS  Google Scholar 

  5. Uren AG, Wong L, Pakusch M et al (2000) Survivin and the inner centromere protein INCENP show similar cell-cycle localization and gene knockout phenotype. Curr Biol 10:1319–1328

    Article  PubMed  CAS  Google Scholar 

  6. Altieri DC (2003) Validating survivin as a cancer therapeutic target. Nat Rev Cancer 3:46–54

    Article  PubMed  CAS  Google Scholar 

  7. Velculescu VE, Madden SL, Zhang L et al (1999) Analysis of human transcriptomes. Nat Genet 23:387–388

    Article  PubMed  CAS  Google Scholar 

  8. Li F, Brattain MG (2006) Role of the survivin gene in pathophysiology. Am J Pathol 169:1–11

    Article  PubMed  CAS  Google Scholar 

  9. Fukuda S, Pelus LM (2006) Survivin, a cancer target with an emerging role in normal adult tissues. Mol Cancer Ther 5:1087–1098

    Article  PubMed  CAS  Google Scholar 

  10. Lechler P, Wu X, Bernhardt W et al (2007) The tumor gene survivin is highly expressed in adult renal tubular cells: implications for a pathophysiological role in the kidney. Am J Pathol 171:1483–1498

    Article  PubMed  CAS  Google Scholar 

  11. Altieri DC (2008) Survivin, cancer networks and pathway-directed drug discovery. Nat Rev Cancer 8:61–70

    Article  PubMed  CAS  Google Scholar 

  12. Altieri DC (2006) The case for survivin as a regulator of microtubule dynamics and cell-death decisions. Curr Opin Cell Biol 18:609–615

    Article  PubMed  CAS  Google Scholar 

  13. Li F, Ackermann EJ, Bennett CF et al (1999) Pleiotropic cell-division defects and apoptosis induced by interference with survivin function. Nat Cell Biol 1:461–466

    Article  PubMed  CAS  Google Scholar 

  14. Dohi T, Beltrami E, Wall NR et al (2004) Mitochondrial survivin inhibits apoptosis and promotes tumorigenesis. J Clin Invest 114:1117–1127

    PubMed  CAS  Google Scholar 

  15. Colnaghi R, Connell CM, Barrett RM, Wheatley SP (2006) Separating the anti-apoptotic and mitotic roles of survivin. J Biol Chem 281:33450–33456

    Article  PubMed  CAS  Google Scholar 

  16. Knauer SK, Kramer OH, Knosel T et al (2007) Nuclear export is essential for the tumor-promoting activity of survivin. FASEB J 21:207–216

    Article  PubMed  CAS  Google Scholar 

  17. Knauer SK, Bier C, Habtemichael N, Stauber RH (2006) The survivin-Crm1 interaction is essential for chromosomal passenger complex localization and function. EMBO Rep 7:1259–1265

    Article  PubMed  CAS  Google Scholar 

  18. Maurin AC, Chavassieux PM, Meunier PJ (2005) Expression of PPARc and b/d in human primary osteoblastic cells: influence of polyunsaturated fatty acids. Calcif Tissue Int 76:385–392

    Article  PubMed  CAS  Google Scholar 

  19. Jilka RL, Weinstein RS, Bellido T, Parfitt AM, Manolagas SC (1998) Osteoblasts programmed cell death (apoptosis): modulation by growth factors and cytokines. J Bone Miner Res 13:793–802

    Article  PubMed  CAS  Google Scholar 

  20. Ling X, Bernacki RJ, Brattain MG, Li F (2004) Induction of survivin expression by Taxol (paclitaxel) is an early event, which is independent of Taxol-mediated G2/M arrest. J Biol Chem 279(15):15196–15203

    Article  PubMed  CAS  Google Scholar 

  21. Kobayashi K, Hatano M, Otaki M, Ogasawara T, Tokuhisa T (1999) Expression of a murine homologue of the inhibitor of apoptosis protein is related to cell proliferation. Proc Natl Acad Sci USA 96:1457–1462

    Article  PubMed  CAS  Google Scholar 

  22. Johnson EA, Svetlov SI, Pike BR et al (2004) Cell-specific upregulation of survivin after experimental traumatic brain injury in rats. J Neurotrauma 21:1183–1195

    Article  PubMed  Google Scholar 

  23. Deguchi M, Shiraki K, Inoue H et al (2002) Expression of survivin during liver regeneration. Biochem Biophys Res Commun 297:59–64

    Article  PubMed  CAS  Google Scholar 

  24. Chiou SK, Tanigawa T, Akahoshi T et al (2005) Survivin: a novel target for indomethacin-induced gastric injury. Gastroenterology 128:63–73

    Article  PubMed  CAS  Google Scholar 

  25. Fortugno P, Beltrami E, Plescia J et al (2003) Regulation of survivin function by Hsp90. Proc Natl Acad Sci USA 100:13791–13796

    Article  PubMed  CAS  Google Scholar 

  26. Bidmon B, Endemann M, Muller T et al (2002) HSP-25 and HSP-90 stabilize Na, K-ATPase in cytoskeletal fractions of ischemic rat renal cortex. Kidney Int 62:1620–1627

    Article  PubMed  CAS  Google Scholar 

  27. Romanello M, Bivi N, Pines A et al (2006) Bisphosphonates activate nucleotide receptors signaling and induce the expression of Hsp90 in osteoblast-like cell lines. Bone 39:739–753

    Article  PubMed  CAS  Google Scholar 

  28. Powers MV, Clarke PA, Workman P (2009) Death by chaperone: HSP90, HSP70 or both? Cell Cycle 8:518–526

    Article  PubMed  CAS  Google Scholar 

  29. Gronowicz GA, McCarthy MB, Zhang H et al (2004) Insulin-like growth factor II induces apoptosis in osteoblasts. Bone 35:621–628

    Article  PubMed  CAS  Google Scholar 

  30. Weinstein RS, Jilka RL, Parfitt AM, Manolagas SC (1998) Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids: potential mechanisms of their deleterious effects on bone. J Clin Invest 102:274–282

    Article  PubMed  CAS  Google Scholar 

  31. Kitajima I, Nakajima T, Imamura T et al (1996) Induction of apoptosis in murine clonal osteoblasts expressed by human T-cell leukeumiavirus type I tax by NF-kappa B and TNF-α. J Bone Miner Res 11:200–210

    Article  PubMed  CAS  Google Scholar 

  32. Tsuboi M, Kawakami A, Nakashima T et al (1999) Tumor necrosis factor-alpha and interleukin-1beta increase the Fas-mediated apoptosis of human osteoblasts. J Lab Clin Med 134:222–231

    Article  PubMed  CAS  Google Scholar 

  33. Chen J, Wu W, Tahir SK et al (2000) Down-regulation of survivin by antisense oligonucleotides increases apoptosis, inhibits cytokinesis and anchorage-independent growth. Neoplasia 2:235–241

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We thank Anja Sabo and Luise Rauch for excellent technical assistance, Dr. Silvia Capellino helped kindly with the fluorescence microscope, and we are grateful to R. Stauber for the kind gift of the human cDNA for survivin. P. L. was supported by the Regensburger Forschungsförderung in der Medizin (ReForM).

Conflict of interest

The authors have stated that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Orthopedic Surgery, University of Regensburg, Asklepios Klinikum Bad Abbach, Kaiser Karl V Allee 3, Bad Abbach, 93077, Germany

    Philipp Lechler, Jens Schaumburger, Franz X. Köck & Joachim Grifka

  2. Renal Section, Division of Immunology and Inflammation (Medicine), Imperial College London, Hammersmith Hospital, London, UK

    Sanjeevi Balakrishnan

  3. Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Erlangen, Germany

    Stavros Doukas

  4. Department of Trauma and Plastic Surgery, University of Regensburg, Regensburg, Germany

    Lukas Prantl

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  1. Philipp Lechler
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  2. Jens Schaumburger
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  3. Franz X. Köck
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  4. Sanjeevi Balakrishnan
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  5. Stavros Doukas
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  7. Joachim Grifka
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Correspondence to Philipp Lechler.

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Lechler, P., Schaumburger, J., Köck, F.X. et al. The Oncofetal Gene Survivin Promotes Cell Proliferation and Survival in Primary Human Osteoblastic Cells. Calcif Tissue Int 89, 211–220 (2011). https://doi.org/10.1007/s00223-011-9508-y

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  • DOI: https://doi.org/10.1007/s00223-011-9508-y

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