Skip to main content
SpringerLink
Log in

Inhibition of adenovirus-mediated human MAGE-D1 on angiogenesis in vitro and in vivo

  • Original Paper
  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

MAGE-D1 is a member of the MAGE family of proteins, and functions as an adaptor that mediates multiple signaling pathways. The current study for the first time provides evidence for a role of MAGE-D1 in the negative regulation of angiogenic activity in vitro and in vivo models. Our findings showed that MAGE-D1 over-expression significantly suppressed the angiogenic key events such as endothelial cell migration and invasion, adhesion on collagen I substrate, and in vitro differentiation into tube-like structures under both normoxic and hypoxic conditions. MAGE-D1 over-expression also inhibited in vivo angiogenesis in Matrigel plugs that were implanted subcutaneously in mice. With further experiments, we revealed that MAGE-D1 over-expression disrupted actin cytoskeleton organization and lamellipodia formation, and down-regulated HIF-1-dependent gene expression in endothelial cells under hypoxic conditions. These findings demonstrate a new function of MAGE-D1 in the regulation of angiogenesis and provide new insight into the ability of MAGE-D1 to suppress the growth and angiogenic response of endothelial cells by interfering with HIF-1-dependent gene expression, and actin cytoskeleton reorganization, suggesting that MAGE-D1 might be a novel inhibitor of angiogenesis in vitro and in vivo.

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
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Auerbach R, Lewis R, Shinners B, Kubai L, Akhtar N (2003) Angiogenesis assays: a critical overview. Clin Chem 49:32–40

    Article  PubMed  CAS  Google Scholar 

  2. Folkman J (2005) Role of angiogenesis in tumor growth and metastasis. Semin Oncol 29:15–18

    Google Scholar 

  3. Giavazzi R, Sennino B, Coltrini D, Garofalo A, Dossi R, Ronca R, Tosatti MP, Presta M (2003) Distinct role of fibroblast growth factor-2 and vascular endothelial growth factor on tumor growth and angiogenesis. Am J Pathol 162:1913–1926

    PubMed  CAS  Google Scholar 

  4. Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86:353–364

    Article  PubMed  CAS  Google Scholar 

  5. Carmeliet P (2000) Mechanisms of angiogenesis and arteriogenesis. Nat Med 6:389–395

    Article  PubMed  CAS  Google Scholar 

  6. Moon HE, Ahn MY, Park JA., Min KJ, Kwon YW, Kim KW (2005) Negative regulation of hypoxia inducible factor-1alpha by necdin. FEBS Lett 579:3797–3801

    Article  PubMed  CAS  Google Scholar 

  7. Milkiewicz M, Ispanovic E, Doyle JL, Haas TL (2006) Regulators of angiogenesis and strategies for their therapeutic manipulation. Int J Biochem Cell Biol 38:333–357

    Article  PubMed  CAS  Google Scholar 

  8. Teicher BA (2005) Hypoxia, tumor endothelium, and targets for therapy. Adv Exp Med Biol 566:31–38

    Article  PubMed  CAS  Google Scholar 

  9. Ruggeri BA, Robinson C, Angeles T, Wilkinson J 4th, Clapper ML (2002) The chemopreventive agent oltipraz possesses potent antiangiogenic activity in vitro, ex vivo, and in vivo and inhibits tumor xenograft growth. Clin Cancer Res 8:267–274

    PubMed  CAS  Google Scholar 

  10. Pepper MS (1997) Manipulating angiogenesis, from basic science to the bedside. Arterioscler Thromb Vasc Biol 17:605–619

    PubMed  CAS  Google Scholar 

  11. Barker PA, Salehi A (2002) The MAGE proteins: emerging roles in cell cycle progression, apoptosis, and neurogenetic disease. J Neurosci Res 67:705–712

    Article  PubMed  CAS  Google Scholar 

  12. Salehi AH, Roux PP, Kubu CJ, Zeindler C, Bhakar A, Tannis LL, Verdi JM, Barker PA (2000) NRAGE, a novel MAGE protein, interacts with the p75 neurotrophin receptor and facilitates nerve growth factor-dependent apoptosis. Neuron 27:279–288

    Article  PubMed  CAS  Google Scholar 

  13. Matsuda Y, Sasaki A, Shibuya H, Ueno N, Ikeda K, Watanabe K (2001) Dlxin-1, a novel protein that binds Dlx5 and regulates its transcriptional function. J Biol Chem 276:5331–5338

    Article  Google Scholar 

  14. Kuwajima T, Taniura H, Nishimura I, Yoshikawa KN (2004) Necdin interacts with the Msx2 homeodomain protein via MAGE-D1 to promote myogenic differentiation of C2C12 cells. J Biol Chem 279:40484–40493

    Article  PubMed  CAS  Google Scholar 

  15. Williams ME, Strickland P, Watanabe K, Hinck L (2003) UNC5H1 induces apoptosis via its juxtamembrane region through an interaction with NRAGE. J Biol Chem 278:17483–18490

    Article  PubMed  CAS  Google Scholar 

  16. Matsuda T, Suzuki H, Oishi I, Kani S, Kuroda Y, Komori T, Sasaki A, Watanabe K, Minami Y (2003) The receptor tyrosine kinase Ror2 associates with the melanoma-associated antigen (MAGE) family protein Dlxin-1 and regulates its intracellular distribution. J Biol Chem 278:29057–29064

    Article  PubMed  CAS  Google Scholar 

  17. Jordan BW, Dinev D, LeMellay V, Troppmair J, Gotz R, Wixler L, Sendtner M, Ludwig, Rapp UR (2001) Neurotrophin receptor-interacting mage homologue is an inducible inhibitor of apoptosis protein-interacting protein that augments cell death. J Biol Chem 276:39985–39989

    Article  PubMed  CAS  Google Scholar 

  18. Sasaki A, Masuda Y, Iwai K, Ikeda K, Watanabe K (2002) A RING finger protein Praja1 regulates Dlx5-dependent transcription through its ubiquitin ligase activity for the Dlx/Msx-interacting MAGE/Necdin family protein Dlxin-1. J Biol Chem 277:22541–22546

    Article  PubMed  CAS  Google Scholar 

  19. Hennuy B, Reiter E, Cornet A, Bruyninx M, Daukandt M, Houssa P, N’Guyen VH, Closset J, Hennen G (2000) A novel messenger ribonucleic acid homologous to human MAGE-D is strongly expressed in rat sertoli cells and weakly in leydig cells and is regulated by follitropin, lutropin, and prolactin. Endocrinology 141:3821–3831

    Article  PubMed  CAS  Google Scholar 

  20. Sasaki A, Hinck L, Watanabe K (2005) RumMAGE-D the members: structure and function of a new adaptor family of MAGE-D proteins. J Recept Signal Transduct Res 25:181–198

    Article  PubMed  CAS  Google Scholar 

  21. Taniura H, Taniguchi N, Hara M, Yoshikawa K (1998) Necdin, a postmitotic neuron-specific growth suppressor, interacts with viral transforming proteins and cellular transcription factor E2F1. J Biol Chem 273:720–728

    Article  PubMed  CAS  Google Scholar 

  22. Aihara M, Sugawara K, Torii S, Hosaka M, Kurihara H, Saito N, Takeuchi T (2004) Angiogenic endothelium-specific nestin expression is enhanced by the first intron of the nestin gene. Lab Invest 84:1581–1592

    Article  PubMed  CAS  Google Scholar 

  23. Wen CJ, Xue B, Qin WX, Yu M, Zhang MY, Zhao DH, Gao X, Gu JR, Li CJ (2004) hNRAGE, a human neurotrophin receptor interacting MAGE homologue, regulates p53 transcriptional activity and inhibits cell proliferation. FEBS Lett 564:171–176

    Article  PubMed  CAS  Google Scholar 

  24. Keledjian K, Kyprianou N (2003) Anoikis induction by quinazoline based alpha 1-adrenoceptor antagonists in prostate cancer cells: antagonistic effect of bcl-2. J Urol 169:1150–1156

    Article  PubMed  CAS  Google Scholar 

  25. Leavesley DI, Schwartz MA, Rosenfeld M, Cheresh DA (1993) Integrin beta 1- and beta 3-mediated endothelial cell migration is triggered through distinct signaling mechanisms. J Cell Biol 121:163–170

    Article  PubMed  CAS  Google Scholar 

  26. Annabi B, Thibeault S, Lee YT, Bousquet-Gagnon N, Eliopoulos N, Barrette S, Galipeau J, Beliveau R (2003) Matrix metalloproteinase regulation of sphingosine-1- phosphate- induced angiogenic properties of bone marrow stromal cells. Exp Hematol 31:640–649

    Article  PubMed  CAS  Google Scholar 

  27. Ashton AW, Yokota R, John G, Zhao S, Suadicani SO, Spray DC, Ware JA (1999) Inhibition of endothelial cell migration, intercellular communication, and vascular tube formation by thromboxane A(2). J Biol Chem 274:35562–35570

    Article  PubMed  CAS  Google Scholar 

  28. Tamilarasan KP, Kolluru GK, Rajaram M, Indhumathy M, Saranya R, Chatterjee S (2006) Thalidomide attenuates nitric oxide mediated angiogenesis by blocking migration of endothelial cells. BMC Cell Biol 7:17

    Article  PubMed  CAS  Google Scholar 

  29. Shibata T, Akiyama N, Noda M, Sasai K, Hiraoka M (1998) Enhancement of gene expression under hypoxic conditions using fragments of the human vascular endothelial growth factor and the erythropoietin genes. Int J Radiat Oncol Biol Phys 42:913–916

    Article  PubMed  CAS  Google Scholar 

  30. Eccles SA (2004) Parallels in invasion and angiogenesis provide pivotal points for therapeutic intervention. Int J Dev Biol 48:583–598

    Article  PubMed  CAS  Google Scholar 

  31. Pore N, Jiang Z, Gupta A, Cerniglia G, Kao GD, Maity A (2006) EGFR tyrosine kinase inhibitors decrease VEGF expression by both hypoxia-inducible factor (HIF)-1 -independent and HIF-1-dependent mechanisms. Cancer Res 66:3197–3204

    Article  PubMed  CAS  Google Scholar 

  32. Kieda C, Greferath R, Crola Da Silva C, Fylaktakidou KC, Lehn JM, Nicolau C (2006) Suppression of hypoxia-induced HIF-1α and of angiogenesis in endothelial cells by myo-inositol trispyrophosphate-treated erythrocytes. Proc Natl Acad Sci USA 103:15576–15581

    Article  PubMed  CAS  Google Scholar 

  33. Lee HT, Kay EP (2003) FGF-2 induced reorganization and disruption of actin cytoskeleton through PI 3-kinase, Rho, and Cdc42 in corneal endothelial cells. Mol Vis 9:624–634

    PubMed  CAS  Google Scholar 

  34. Barrett GL, Greferath U, Barker PA, Trieu J, Bennie A (2005) Co-expression of the P75 neurotrophin receptor and neurotrophin receptor-interacting melanoma antigen homolog in the mature rat brain. Neuroscience 133:381–392

    Article  PubMed  CAS  Google Scholar 

  35. Chomez P, De Backer O, Bertrand M, De Plaen M, Boon T, Lucas S (2001) An overview of the MAGE gene family with the identification of all human members of the family. Cancer Res 61:5544–5551

    PubMed  CAS  Google Scholar 

  36. Ettenson DS, Gotlieb AI (1994) Endothelial wounds with disruption in cell migration repair primarily by cell proliferation. Microvasc Res 48:328–337

    Article  PubMed  CAS  Google Scholar 

  37. Pugh CW, Ratcliffe PJ (2003) Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med 9:677–684

    Article  PubMed  CAS  Google Scholar 

  38. Kim HS, Skurk C, Thomas SR, Bialik A, Suhara T, Kureishi Y, Birnbaum M, Jr. Keaney JF, Walsh K (2002) Regulation of angiogenesis by glycogen synthase kinase-3beta. J Biol Chem 277: 41888–41896

    Article  PubMed  CAS  Google Scholar 

  39. Hall A (1998) Rho GTPases and the actin cytoskeleton. Science 279:509–514

    Article  PubMed  CAS  Google Scholar 

  40. Ridley AJ (2001) Rho GTPases and cell migration. J Cell Sci 114:2713–2722

    PubMed  CAS  Google Scholar 

  41. Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM (2003) Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 3:347–361

    Article  PubMed  Google Scholar 

  42. Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, Capla JM, Galiano RD, Levine JP, Gurtner GC (2004) Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 10:858–864

    Article  PubMed  CAS  Google Scholar 

  43. Semenza GL (2001) Regulation of hypoxia-induced angiogenesis: a chaperone escorts VEGF to the dance. J Clin Invest 108:39–40

    Article  PubMed  CAS  Google Scholar 

  44. Harris AL (2002) Hypoxia–a key regulatory factor in tumour growth. Nat Rev Cancer 2:38–47

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank Prof. M. Hiraoka for 5×HRE/pGL3/VEGF/E1b. This work was supported in part by grants from Natural Science Foundation of the Department of Education of Jiangsu Province and the project of the Subjects Group for Life Science of Yangzhou University (China).

Author information

Authors and Affiliations

  1. Medical College of Yangzhou University, 16 Huai Hai Road, Yangzhou, 225000, Jiangsu Province, PR China

    Wei-Gan Shen, Jun Zhu, Ben-Shun Hu, Yu Zhang, Yi-Ding Wu & Qing Su

  2. Yangzhou Educational College, Yangzhou, PR China

    Qing-Yu Xue

Authors
  1. Wei-Gan Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qing-Yu Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jun Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ben-Shun Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yi-Ding Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Qing Su
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wei-Gan Shen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shen, WG., Xue, QY., Zhu, J. et al. Inhibition of adenovirus-mediated human MAGE-D1 on angiogenesis in vitro and in vivo. Mol Cell Biochem 300, 89–99 (2007). https://doi.org/10.1007/s11010-006-9373-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-006-9373-6

Keywords

Search

Navigation