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Release of an inhibitor of angiogenesis upon induction of wild type p53 expression in glioblastoma cells

Nature Genetics volume 8, pages 171–176 (1994)Cite this article

Abstract

The earliest genetic alteration in human astrocytoma progression is mutation of the p53 tumour suppressor gene, while one of the earliest phenotypic changes is the stimulation of neovascularization. Here, we tested the role of p53 in the angiogenic process by introducing a tetracycline-regulated wild type p53 gene into null glioblastoma cells. The parental cells expressed strong angiogenic activity while upon induction of wild type, but not mutant, p53 expression, the cells secreted a factor able to neutralize the angiogenicity of the factors produced by the parental cells as well as of basic fibroblast growth factor.

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References

  1. Folkman, J. & Klagsbrun, M. Angiogenic factors. Science 235, 442–447 (1987).

    Article  CAS  Google Scholar 

  2. Folkman, J., Long, D.M. & Becker, F.F. Growth and metastasis of tumor in organ culture. Cancer 16, 453 (1963).

    Article  CAS  Google Scholar 

  3. Fearon, E.R. & Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 61, 759–767 (1990).

    Article  CAS  Google Scholar 

  4. Brem, S., Cotran, R. & Folkman, J. Tumor angiogenesis: a quantitative method for histologic grading. J. natn. Cancer Inst. 48, 347–356 (1972).

    CAS  Google Scholar 

  5. Russell, D.C. & Rubinstein, L J. Pathology of tumours of the nervous system. (Edward Arnold, London, 1989).

    Google Scholar 

  6. Cavenee, W.K., Scrable, H.J. & James, C.D. Molecular genetics of human cancer predisposition and progression. Mutat. Res. 247, 199–202 (1991).

    Article  CAS  Google Scholar 

  7. Nigro, J.M. et al. Mutations in the p53 gene occur in diverse human tumour types. Nature 342, 705–708 (1989).

    Article  CAS  Google Scholar 

  8. Sidransky, D. et al. Clonal expansion of p53 mutant cells is associated with brain tumour progression. Nature 355, 846–847 (1992).

    Article  CAS  Google Scholar 

  9. Hollstein, M., Sidransky, D., Vogelstein, B. & Harris, C.C. p53 mutations in human cancers. Science 253, 49–53 (1991).

    Article  CAS  Google Scholar 

  10. Levine, A.J., Momand, J. & Finlay, C.A. The p53 tumour suppressor gene. Nature 351, 453–456 (1991).

    Article  CAS  Google Scholar 

  11. Lane, D.P. P53, guardian of the genome. Nature 358, 15–16 (1992).

    Article  CAS  Google Scholar 

  12. Kern, S.E. et al. Identification of p53 as a sequence-specific DNA-binding protein. Science 252, 1708–1711 (1991).

    Article  CAS  Google Scholar 

  13. Ginsberg, D., Mechta, F., Yaniv, M. & Oren, M. Wild-type p53 can down-modulate the activity of various promoters. Proc. natn. Acad. Sci. U.S.A. 88, 9979–9983 (1991).

    Article  CAS  Google Scholar 

  14. Farmer, G. et al. Wild-type p53 activates transcription in vitro . Nature 358, 83–86 (1992).

    Article  CAS  Google Scholar 

  15. Cho, Y., Gorina, S., Jeffrey, P.D. & Pavletich, N.P. Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science 265, 346–355 (1994).

    Article  CAS  Google Scholar 

  16. Baker, S.J., Markowitz, S., Fearon, E.R., Wilson, J.K. & Vogelstein, B. Suppression of human colorectal carcinoma cell growth by wild-type p53. Science 249, 912–915 (1990).

    Article  CAS  Google Scholar 

  17. Martinez, J., Georgoff, I., Martinez, J. & Levine, A.J. Cellular localization and cell cycle regulation by a temperate-sensitive p53 protein. Genes Dev. 5, 151–159 (1991).

    Article  CAS  Google Scholar 

  18. Diller, L. et al. p53 functions as a cell cycle control protein in osteosarcomas. Molec. cell. Biol. 10, 5772–5781 (1990).

    Article  CAS  Google Scholar 

  19. Kastan, M.B., Onyekwere, O., Sidransky, D., Vogelstein, B. & Craig, R.W. Participation of p53 protein in the cellular response to DNA damage. Cancer Res. 51, 6304–6311 (1991).

    CAS  Google Scholar 

  20. Yin, Y., Tainsky, M.A., Bischoff, F.Z., Strong, L.C. & Wahl, G.M. Wild-type p53 restores cell cycle control and inhibits gene amplification in cells with mutant p53 alleles. Cell 70, 937–948 (1992).

    Article  CAS  Google Scholar 

  21. Livingstone, L.R. et al. Altered cell cycle arrest and gene amplicication potential accompany loss of wild-type p53. Cell 70, 923–935 (1992).

    Article  CAS  Google Scholar 

  22. Kemp, C.J., Donehower, L.A., Bradley, A. & Balmain, A. Reduction of p53 gene dosage does not increase initiation or promotion but enhances malignant progression of chemically induced skin tumors. Cell 74, 813–822 (1993).

    Article  CAS  Google Scholar 

  23. Malkin, D. et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcoma and other neoplasms. Science 250, 1233–1238 (1990).

    Article  CAS  Google Scholar 

  24. Srivastava, S., Zou, Z.Q., Pirollo, K., Blattner, W. & Chang, E.H. Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni Syndrome. Nature 348, 747–749 (1990).

    Article  CAS  Google Scholar 

  25. Gossen, M. & Bujard, H. Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc. natn. Acad. Sci. U.S.A. 89, 5547–5551 (1992).

    Article  CAS  Google Scholar 

  26. Van Meir, E.G. et al. Analysis of the p53 gene and its expression in human glioblastoma cells. Cancer Res. 54, 649–652 (1994).

    CAS  PubMed  Google Scholar 

  27. EI-Deiry, W.S. et al. WAF1, a potential mediator of p53 tumor suppression. Cell 75, 817–825 (1993).

    Article  Google Scholar 

  28. Glaser, B.M., D'Amore, P.A., Seppa, H. & Schiffmann, E. Adult tissues contain chemottractants for vascular endothelial cells. Nature 288, 483–484 (1980).

    Article  CAS  Google Scholar 

  29. Rastinejad, F., Polverini, P.J. & Bouck, N.P. Regulation of the activity of a new inhibitor of angiogenesis by a cancer suppressor gene. Cell 56, 345–355 (1989).

    Article  CAS  Google Scholar 

  30. Gall, C.M. in Astrocytomas: diagnosis, treatment, and biology (eds Black, P.M., Schoene, W.C. & Lampson, L.A.) 241–249 (Blackwell Scientific Publications, Boston, 1991).

    Google Scholar 

  31. Klagsbrun, M. & D'Amore, P.A. Regulators of angiogenesis. A. Rev. Physiol. 53, 217–239 (1991).

    Article  CAS  Google Scholar 

  32. Plate, K.H., Breier, G., Weich, H.A. & Risau, W. Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 359, 845–848 (1992).

    Article  CAS  Google Scholar 

  33. Shweiki, D., Itin, A., Softer, D. & Keshet, E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359, 843–845 (1992).

    Article  CAS  Google Scholar 

  34. Kim, K.J. et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo . Nature 362, 841–844 (1993).

    Article  CAS  Google Scholar 

  35. Kern, S.E. et al. Oncogenic forms of p53 inhibit p53-regulated gene expression. Science 256, 827–830 (1992).

    Article  CAS  Google Scholar 

  36. Good, D.J. et al. A tumor suppressor-dependent inhibitor of angiogenesis is immunologically and functionally indistinguishable from a fragment of thrombospondin. Proc. natn. Acad. Sci. U.S.A. 87, 6624–6628 (1990).

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Ludwig Institute for Cancer Research;, University of California at San Diego, La Jolla, California, 92093-0660, USA

    Erwin G. Van Meir, Victoria R. Chazin, H.-J. Su Huang & Webster K. Cavenee

  2. Laboratory of Tumour Biology and Genetics, Neurosurgery Service, University Hospital (CHUV), Lausanne, 1011, Switzerland

    Erwin G. Van Meir & Nicolas de Tribolet

  3. School of Dentistry, University of Michigan, Ann Arbor, Michigan, 48109-1078, USA

    Peter J. Polverini

  4. Department of Medicine, University of California at San Diego, La Jolla, California, 92093-0660, USA

    H.-J. Su Huang & Webster K. Cavenee

  5. Center for Molecular Genetics, University of California at San Diego, La Jolla, California, 92093-0660, USA

    Webster K. Cavenee

Authors
  1. Erwin G. Van Meir
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  2. Peter J. Polverini
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  3. Victoria R. Chazin
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  4. H.-J. Su Huang
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  5. Nicolas de Tribolet
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  6. Webster K. Cavenee
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Van Meir, E., Polverini, P., Chazin, V. et al. Release of an inhibitor of angiogenesis upon induction of wild type p53 expression in glioblastoma cells. Nat Genet 8, 171–176 (1994). https://doi.org/10.1038/ng1094-171

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