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Anoxia induces macrophage inhibitory cytokine-1 (MIC-1) in glioblastoma cells independently of p53 and HIF-1

Oncogene volume 21, pages 4212–4219 (2002)Cite this article

Abstract

Human astrocytic brain tumors select for mutations in the p53 tumor suppressor gene early in malignant progression. p53 is activated upon various kinds of cellular stress leading to apoptosis or cell cycle arrest, but is also implicated in complex biological processes such as inhibition of angiogenesis and metastasis. In an effort to shed light on consequences mediated by p53 inactivation in gliomas, we established the Tet-On system for p53 in the LN-Z308 glioblastoma cell line. The macrophage inhibitory cytokine-1 (MIC-1) gene was identified as a most prominent p53 target gene upon gene expression profiling. Oxygen deprivation, an important cellular stress, revealed MIC-1 as an anoxia responsive gene in glioblastoma cell lines. MIC-1 up-regulation by anoxia is mediated through an alternative, p53 and hypoxia inducible factor 1 (HIF-1) independent pathway. Furthermore, ectopic expression of MIC-1 in LN-Z308 cell line completely abolished its inherent tumorigenicity in nude mice, while proliferation in vitro was not affected. In the present experimental model MIC-1 may exert its anti-tumorigenic properties via a paracrine mechanism mediated by host cells in vivo. Taken together, these data suggest that MIC-1 is an important downstream mediator of p53 function, while acting itself as an intercessor of cellular stress signaling and exerting anti-tumorigenic activities.

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References

  • Albertoni M, Daub DM, Arden KC, Viars CS, Powell C, Van ME . 1998 Oncogene 16: 321–326

  • An WG, Kanekal M, Simon MC, Maltepe E, Blagosklonny MV, Neckers LM . 1998 Nature 392: 405–408

  • Baek SJ, Horowitz JM, Eling TE . 2001a J. Biol. Chem. 276: 33384–33392

  • Baek SJ, Kim KS, Nixon JB, Wilson LC, Eling TE . 2001b Mol. Pharmacol. 59: 901–908

  • Bauskin AR, Zhang HP, Fairlie WD, He XY, Russell PK, Moore AG, Brown DA, Stanley KK, Breit SN . 2000 EMBO J. 19: 2212–2220

  • Bonnekoh B, Wevers A, Jugert F, Merk H, Mahrle G . 1989 Arch. Dermatol. Res. 281: 487–490

  • Bootcov MR, Bauskin AR, Valenzuela SM, Moore AG, Bansal M, He XY, Zhang HP, Donnellan M, Mahler S, Pryor K, Walsh BJ, Nicholson RC, Fairlie WD, Por SB, Robbins JM, Breit SN . 1997 Proc. Natl. Acad. Sci. USA 94: 11514–11519

  • Bottner M, Laaff M, Schechinger B, Rappold G, Unsicker K, Suter-Crazzolara C . 1999 Gene 237: 105–111

  • Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K, Dewerchin M, Neeman M, Bono F, Abramovitch R, Maxwell P, Koch CJ, Ratcliffe P, Moons L, Jain RK, Collen D, Keshert E, Keshet E . 1998 Nature 394: 485–490

  • Chandel NS, Maltepe E, Goldwasser E, Mathieu CE, Simon MC, Schumacker PT . 1998 Proc. Natl. Acad. Sci. USA 95: 11715–11720

  • Chandel NS, Vander Heiden MG, Thompson CB, Schumacker PT . 2000 Oncogene 19: 3840–3848

  • Desbaillets I, Diserens AC, de Tribolet N, Hamou MF, Van Meir EG . 1999 Oncogene 18: 1447–1456

  • Desbaillets I, Diserens AC, Tribolet N, Hamou MF, Van Meir EG . 1997 J. Exp. Med. 186: 1201–1212

  • Detmer K, Steele TA, Shoop MA, Dannawi H . 1999 Blood Cells Mol. Dis. 25: 310–323

  • el-Deiry WS, Harper JW, O'Connor PM, Velculescu VE, Canman CE, Jackman J, Pietenpol JA, Burrell M, Hill DE, Wang Y . 1994 Cancer Res. 54: 1169–1174

  • Fairlie WD, Moore AG, Bauskin AR, Russell PK, Zhang HP, Breit SN . 1999 J. Leukoc. Biol. 65: 2–5

  • Fairlie WD, Russell PK, Wu WM, Moore AG, Zhang HP, Brown PK, Bauskin AR, Breit SN . 2001 Biochemistry 40: 65–73

  • Gossen M, Bujard H . 1992 Proc. Natl. Acad. Sci. USA 89: 5547–5551

  • Gossen M, Freundlieb S, Bender G, Muller G, Hillen W, Bujard H . 1995 Science 268: 1766–1769

  • Hromas R, Hufford M, Sutton J, Xu D, Li Y, Lu L . 1997 Biochim. Biophys. Acta 1354: 40–44

  • Hsiao EC, Koniaris LG, Zimmers-Koniaris T, Sebald SM, Huynh TV, Lee SJ . 2000 Mol. Cell. Biol. 20: 3742–3751

  • Ishii N, Maier D, Merlo A, Tada M, Sawamura Y, Diserens AC, Van Meir EG . 1999 Brain Pathol. 9: 469–479

  • Kannan K, Amariglio N, Rechavi G, Givol D . 2000 FEBS Lett. 470: 77–82

  • Kessler R, Hamou MF, Albertoni M, de Tribolet N, Arand M, Van Meir EG . 2000 Cancer Res. 60: 1403–1409

  • Lawton LN, Bonaldo MF, Jelenc PC, Qiu L, Baumes SA, Marcelino RA, de Jesus GM, Wellington S, Knowles JA, Warburton D, Brown S, Soares MB . 1997 Gene 203: 17–26

  • Levine AJ . 1997 Cell 88: 323–331

  • Li PX, Wong J, Ayed A, Ngo D, Brade AM, Arrowsmith C, Austin RC, Klamut HJ . 2000 J. Biol. Chem. 275: 20127–20135

  • Mandriota SJ, Menoud PA, Pepper MS . 1996 J. Biol. Chem. 271: 11500–11505

  • Mercer WE, Shields MT, Amin M, Sauve GJ, Appella E, Romano JW, Ullrich SJ . 1990 Proc. Natl. Acad. Sci. USA 87: 6166–6170

  • Morgenstern JP, Land H . 1990 Nucleic Acids Res. 18: 1068

  • Numayama-Tsuruta K, Kobayashi A, Sogawa K, Fujii-Kuriyama Y . 1997 Eur. J. Biochem. 246: 486–495

  • Paralkar VM, Vail AL, Grasser WA, Brown TA, Xu H, Vukicevic S, Ke HZ, Qi H, Owen TA, Thompson DD . 1998 J. Biol. Chem. 273: 13760–13767

  • Pepper MS, Vassalli JD, Orci L, Montesano R . 1993 Exp. Cell Res. 204: 356–363

  • Plate KH, Breier G, Weich HA, Risau W . 1992 Nature 359: 845–848

  • Salceda S, Beck I, Caro J . 1996 Arch. Biochem. Biophys. 334: 389–394

  • Schober A, Bottner M, Strelau J, Kinscherf R, Bonaterra GA, Barth M, Schilling L, Fairlie WD, Breit SN, Unsicker K . 2001 J. Comp. Neurol. 439: 32–45

  • Schwarte-Waldhoff I, Volpert OV, Bouck NP, Sipos B, Hahn SA, Klein-Scory S, Luttges J, Kloppel G, Graeven U, Eilert-Micus C, Hintelmann A, Schmiegel W . 2000 Proc. Natl. Acad. Sci. USA 97: 9624–9629

  • Strelau J, Sullivan A, Bottner M, Lingor P, Falkenstein E, Suter-Crazzolara C, Galter D, Jaszai J, Krieglstein K, Unsicker K . 2000 J. Neurosci. 20: 8597–8603

  • Tan M, Wang Y, Guan K, Sun Y . 2000 Proc. Natl. Acad. Sci. USA 97: 109–114

  • Tenan M, Fulci G, Albertoni M, Diserens AC, Hamou MF, El Atifi-Borel M, Feige JJ, Pepper MS, Van Meir EG . 2000 J. Exp. Med. 191: 1789–1798

  • Van Meir EG, Polverini PJ, Chazin VR, Su Huang HJ, de Tribolet N, Cavenee WK . 1994 Nat. Genet. 8: 171–176

  • Whitman M . 1998 Genes Dev. 12: 2445–2462

  • Yamada N, Kato M, Yamashita H, Nister M, Miyazono K, Heldin CH, Funa K . 1995 Int. J. Cancer 62: 386–392

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Acknowledgements

We would like to thank Curzio Rüegg for helpful discussions and critical reading of the manuscript. We are indebted to M Gossen and H Bujard for providing the plasmids necessary to establish the Tet-On System. We are grateful to T Friedmann for the plasmid pLSHL, and to WE Mercer for the p53-inducible cell line GM47-23. This work was made possible by generous support from the Swiss Cancer Research Foundation, KFS-728-9-1998 (to ME Hegi) and KFS-904-9-1999 (to N de Tribolet) and the Swiss National Science Foundation, grants 31-51681 (to N de Tribolet) and 31-49194 (to EG Van Meir) and 31-64050 (to ME Hegi).

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Authors and Affiliations

  1. Department of Neurosurgery, Laboratory of Tumor Biology and Genetics, University Hosptial Lausanne, Lausanne, 1011, Switzerland

    Michele Albertoni, Michimasa Nozaki, Sophie Godard, Mirna Tenan, Marie-France Hamou, Nicolas de Tribolet, Erwin G Van Meir & Monika E Hegi

  2. Laboratory of Experimental Oncology, Institute of Pathology, University of Lausanne, Lausanne, 1011, Switzerland

    Phillip H Shaw

  3. Centre for Immunology St Vincent's Hospital and University of South Wales, Sydney, 2010, NSW, Australia

    Douglas W Fairlie & Samuel N Breit

  4. Pfizer Central Research, Groton, 06340, Connecticut, CT, USA

    Vishwas M Paralkar

  5. Neurosurgery Department and Winship Cancer Institute, Laboratory of Molecular Neuro-Oncology, Emory University, Atlanta, 30322, Georgia, GA, USA

    Erwin G Van Meir

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  1. Michele Albertoni
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  2. Phillip H Shaw
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Correspondence to Monika E Hegi.

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Albertoni, M., Shaw, P., Nozaki, M. et al. Anoxia induces macrophage inhibitory cytokine-1 (MIC-1) in glioblastoma cells independently of p53 and HIF-1. Oncogene 21, 4212–4219 (2002). https://doi.org/10.1038/sj.onc.1205610

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