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The effects of markedly raised intracellular sphingosine kinase-1 activity in endothelial cells

Cellular & Molecular Biology Letters volume 14, pages 411–423 (2009)Cite this article

Abstract

The enzyme sphingosine kinase-1 (SK1) promotes the formation of sphingosine-1-phosphate (S1P), which is an important survival factor for endothelial cells (EC). Modest increases in intracellular SK1 activity in the EC are known to confer a survival advantage upon the cells. Here, we investigated the effects of more dramatic increases in intracellular SK1 in the EC. We found that these cells show reduced cell survival under conditions of stress, enhanced caspase-3 activity, cell cycle inhibition, and cell-cell junction disruption. We propose that alterations in the phosphorylation state of the enzyme may explain the differential effects on the phenotype with modest versus high levels of enforced expression of SK1. Our results suggest that SK1 activity is subject to control in the EC, and that this control may be lost in conditions involving vascular regression.

Abbreviations

EC:

endothelial cell

EV:

empty vector

HUVEC:

human umbilical vein endothelial cell

PECAM-1:

platelet-endothelial cell adhesion molecule-1

pfu:

plaque-forming unit

SK1:

sphingosine kinase-1 (SK1)

S1P:

sphingosine 1-phosphate

TNF:

tumour necrosis factor

References

  1. Kwon, Y.G., Min, J.K., Kim, K.M., Lee, D.J., Billiar, T.R. and Kim, Y.M. Sphingosine 1-phosphate protects human umbilical vein endothelial cells from serum-deprived apoptosis by nitric oxide production. J. Biol. Chem. 276 (2001) 10627–10633.

    Article  PubMed  CAS  Google Scholar 

  2. Wang, F., Van Brocklyn, J.R., Hobson, J.P., Movafagh, S., Zukowska-Grojec, Z., Milstien, S. and Spiegel, S. Sphingosine 1-phosphate stimulates cell migration through a G(i)- coupled cell surface receptor. Potential involvement in angiogenesis. J. Biol. Chem. 274 (1999) 35343–35350.

    Article  PubMed  CAS  Google Scholar 

  3. Lee, M.J., Van Brocklyn, J.R., Thangada, S., Liu, C.H., Hand, A.R., Menzeleev, R., Spiegel, S. and Hla, T. Sphingosine-1-phosphate as a ligand for the G protein-coupled receptor EDG-1. Science 279 (1998) 1552–1555.

    Article  PubMed  CAS  Google Scholar 

  4. Ghosh, T.K., Bian, J. and Gill, D.L. Intracellular calcium release mediated by sphingosine derivatives generated in cells. Science 248 (1990) 1653–1656.

    Article  PubMed  CAS  Google Scholar 

  5. Desai, N.N., Zhang, H., Olivera, A., Mattie, M.E. and Spiegel, S. Sphingosine-1-phosphate, a metabolite of sphingosine, increases phosphatidic acid levels by phospholipase D activation. J. Biol. Chem. 267 (1992) 23122–23128.

    PubMed  CAS  Google Scholar 

  6. Limaye, V., Li, X., Hahn, C., Xia, P., Berndt, M.C., Vadas, M.A. and Gamble, J.R. Sphingosine kinase-1 enhances endothelial cell survival through a PECAM-1-dependent activation of PI-3K/Akt and regulation of Bcl-2 family members. Blood. 105 (2005) 3169–3177.

    Article  PubMed  CAS  Google Scholar 

  7. Evans, P.C., Taylor, E.R. and Kilshaw, P.J. Signaling through CD31 protects endothelial cells from apoptosis. Transplantation 71 (2001) 457–460.

    Article  PubMed  CAS  Google Scholar 

  8. Xia, P., Gamble, J.R., Wang, L., Pitson, S.M., Moretti, P.A., Wattenberg, B.W., D’Andrea, R.J. and Vadas, M.A. An oncogenic role of sphingosine kinase. Curr. Biol. 10 (2000) 1527–1530.

    Article  PubMed  CAS  Google Scholar 

  9. Cramer, E.M., Berger, G. and Berndt, M.C. Platelet-granule and plasma membrane share two components: CD9 and PECAM-1. Blood 84 (1994) 1722–1730.

    PubMed  CAS  Google Scholar 

  10. Litwin, M., Clark, K., Noack, L., Furze, J., Berndt, M., Albelda, S., Vadas, M., and Gamble, J.R. Novel cytokine-independent induction of endothelial adhesion molecules regulated by platelet/endothelial cell adhesion molecule (CD31). J. Cell. Biol. 139 (1997) 219–228.

    Article  PubMed  CAS  Google Scholar 

  11. Pitson, S.M., Moretti, P.A.B., Zebol, J.R., Lynn, H.E., Xia, P., Vadas, M.A., Wattenberg, B.W. Activation of sphingosine kinase 1 by ERK1/2-mediated phosphorylation. EMBO J. 22 (2003) 5491–5500.

    Article  PubMed  CAS  Google Scholar 

  12. Xia, P., Gamble, J.R., Rye, K.A., Wang, L., Hii, C.S., Cockerill, P., Khew-Goodall, Y., Bert, A.G., Barter, P.J., and Vadas, M.A. Tumor necrosis factor-alpha induces adhesion molecule expression through the sphingosine kinase pathway. Proc. Natl. Acad. Sci. USA 95 (1998) 14196–14201.

    Article  PubMed  CAS  Google Scholar 

  13. Spiegel, S., Olivera, A., Zhang, H., Thompson, E.W., Su, Y. and Berger, A. Sphingosine-1-phosphate, a novel second messenger involved in cell growth regulation and signal transduction, affects growth and invasiveness of human breast cancer cells. Breast Cancer Res. Treat. 31 (1994) 337–348.

    Article  PubMed  CAS  Google Scholar 

  14. Pitson, S.M., Moretti, P.A., Zebol, J.R., Xia, P., Gamble, J.R., Vadas, M.A., D’Andrea, R.J. and Wattenberg, B.W. Expression of a catalytically inactive sphingosine kinase mutant blocks agonist-induced sphingosine kinase activation. A dominant-negative sphingosine kinase. J. Biol. Chem. 275 (2000) 33945–33950.

    Article  PubMed  CAS  Google Scholar 

  15. Limaye, V., Xia, P., Hahn, C., Smith, M., Vadas, M.A, Pitson, S.M. and Gamble, J.R. Chronic increases in sphingosine kinase-1 activity induce a pro-inflammatory, pro-angiogenic phenotype in endothelial cells. Cell. Mol. Biol. Lett. 14 (2009) in press, DOI: 10.2478/s11658-009-0009-1.

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Authors and Affiliations

  1. Royal Adelaide Hospital, Department of Rheumatology, North Tce, Royal Adelaide Hospital, Adelaide, SA, 5000, Australia

    Vidya Limaye

  2. Division of Human Immunology, Institute of Medical and Veterinary Science, Frome Road, Adelaide, SA, 5000, Australia

    Vidya Limaye & Stuart M. Pitson

  3. Department of Medicine, University of Adelaide, Frome Rd, Adelaide, SA, Australia

    Vidya Limaye

  4. Centenary Institute, University of Sydney, NSW, Sydney, Australia

    Mathew A. Vadas & Jennifer R. Gamble

  5. School of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia

    Stuart M. Pitson

Authors
  1. Vidya Limaye
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  2. Mathew A. Vadas
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  3. Stuart M. Pitson
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  4. Jennifer R. Gamble
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Correspondence to Vidya Limaye.

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Limaye, V., Vadas, M.A., Pitson, S.M. et al. The effects of markedly raised intracellular sphingosine kinase-1 activity in endothelial cells. Cell Mol Biol Lett 14, 411–423 (2009). https://doi.org/10.2478/s11658-009-0008-2

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  • DOI: https://doi.org/10.2478/s11658-009-0008-2

Key words

Cellular & Molecular Biology Letters

ISSN: 1689-1392

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