Medical Oncology

, Volume 24, Issue 4, pp 436–444

Position-dependent expression of GADD45α in rat brain tumours

  • Antonio Brú
  • Carlos del Fresno
  • Alessandra Soares-Schanoski
  • Sonia Albertos
  • Isabel Brú
  • Amelia Porres
  • Eduardo Rollán-Landeras
  • Ana Dopazo
  • David Casero
  • Vanesa Gómez-Piña
  • Lourdes García
  • Francisco Arnalich
  • Rebeca Alvarez
  • Alexandro Rodríguez-Rojas
  • Pablo Fuentes-Prior
  • Eduardo López-Collazo
Original Paper

Abstract

Although the complex and multifactorial process of tumour growth has been extensively studied for decades, our understanding of the fundamental relationship between tumour growth dynamics and genetic expression profile remains incomplete. Recent studies of tumour dynamics indicate that gene expression in solid tumours would depend on the distance from the centre of the tumour. Since tumour proliferative activity is mainly localised to its external zone, and taking into account that generation and expansion of genetic mutations depend on the number of cell divisions, important differences in gene expression between central and peripheral sections of the same tumour are to be expected. Here, we have studied variations in the genetic expression profile between peripheral and internal samples of the same brain tumour. We have carried out microarray analysis of mRNA expression, and found a differential profile of genetic expression between the two cell subsets. In particular, one major nuclear protein that regulates cell responses to DNA-damaging and stress signals, GADD45α, was expressed at much lower levels in the peripheral zone, as compared to tumour core samples. These differences in GADD45α mRNA transcription levels have been confirmed by quantitative analysis via real time PCR, and protein levels of GADD45α also exhibit the same pattern of differential expression. Our findings suggest that GADD45α might play a major role in the regulation of brain tumour invasive potential.

Keywords

Tumour growth GADD45α p21 

Abbreviation

GADD45α

Growth arrest and DNA-damage-inducible gene 45α

References

  1. 1.
    Brú A, Pator JM, Fernaud I, Melle S, Berenguer C. Super-rough dynamics on tumor growth. Phys Rev Lett 1998;81:4008–11.CrossRefGoogle Scholar
  2. 2.
    Brú A, Albertos S, Subiza JL, Lopez Garcia-Asenjo JA, Brú I. The universal dynamics of tumor growth. Biophys J 2003;85:2948–61.PubMedCrossRefGoogle Scholar
  3. 3.
    Brú A, Albertos S, Lopez Garcia-Asenjo JA, Brú I. Pinning of tumoral growth by enhancement – of the immune response. Phys Rev Lett 2004;92:238101–4.PubMedCrossRefGoogle Scholar
  4. 4.
    Kim Y, Liu XS, Liu C, Smith DE, Russel RM, Wang XD. Induction of pulmonary neoplasia in the smoke-exposed ferret by 4-(methylnitrosamino)-1-(3-pyridil)-1-butanone (NNK): a model for human lung cancer. Cancer Lett 2006;236:209–19.CrossRefGoogle Scholar
  5. 5.
    Lai Z, Das Sarma S. Kinetic growth with surface relaxation: continuum versus atomistic models. Phys Rev Lett 1991;66:2348–51.PubMedCrossRefGoogle Scholar
  6. 6.
    Schneider G, Weber A, Zechner U, Oswald F, Friess HM, Schmid RM, et al. GADD45a is highly expressed in pancreatic ductal adenocarcinoma cells and required for tumor cell viability. Int J Cancer 2005;118:2405-11.CrossRefGoogle Scholar
  7. 7.
    Fornace Jr AJ, Alamo I, Hollander MC. DNA damage-inducible transcripts in mammalian cells. Proc Natl Acad Sci 1988;85:8800–4.PubMedCrossRefGoogle Scholar
  8. 8.
    Fornace Jr AJ. Mammalian genes induced by radiation; activation of genes associated with growth control. Ann Rev Gen 1992;26:507–26.Google Scholar
  9. 9.
    Dotto GP. p21WAF1/Cip1: more than a break to the cell cycle? Biochem Biophys Acta 2000;1471:43–56.Google Scholar
  10. 10.
    Smith ML, Chen IT, Zhan Q, Bae I, Chen CY, Gilmer TM, et al. Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen. Science 1994;266:1376–80.PubMedCrossRefGoogle Scholar
  11. 11.
    Kearsey JM, Coates PJ, Prescott AR, Warbrick E, Hall PA. Gadd45 is a nuclear cell cycle regulated protein which interacts with p21Cip1. Oncogene 1995;11:1675–83.PubMedGoogle Scholar
  12. 12.
    Zhan Q, Antinore MJ, Wang XW, Carrier F, Smith ML, Harris CC, et al. Association with Cdc2 and inhibition of Cdc2/Cyclin B1 kinase activity by the p53-regulated protein Gadd45. Oncogene 1999;18:2892–900.PubMedCrossRefGoogle Scholar
  13. 13.
    Mita H, Tsutsui J, Takekawa M, Witten EA, Saito H. Regulation of MTK1/MEKK4 kinase activity by its N-terminal autoinhibitory domain and GADD45 binding. Mol Cell Biol 2002;22:4544–55.PubMedCrossRefGoogle Scholar
  14. 14.
    Bulavin DV, Kovalsky O, Hollander MC, Fornace Jr AJ. Loss of oncogenic H-ras-induced cell cycle arrest and p38 mitogen-activated protein kinase activation by disruption of Gadd45α. Mol Cell Biol 2003;23(11):3859–71.PubMedCrossRefGoogle Scholar
  15. 15.
    Jin S, Tong T, Fan W, Fan F, Antinore MJ, Zhu X, et al. GADD45-induced cell cycle G2-M arrest associates with altered subcellular distribution of cyclin B1 and is independent of p38 kinase activity. Oncogene 2002;21:8696–704.PubMedCrossRefGoogle Scholar
  16. 16.
    Morrone F, Olivera D, Gamermann P, Stella J, Wofchuck S, Wink M, et al. In vivo glioblastoma growth is reduced by apyrase activity in rat glioma model. BMC Cancer 2006;6:1–10.CrossRefGoogle Scholar
  17. 17.
    Griscelli F, Li H, Bennaceur-Griscelli A, Sorias J, Opolon P, Soria C, et al. Angiostatin gene transfer: inhibition of tumor growth in vivo by blockage of endothelial cell proliferation associated with a mitosis arrest. Proc Natl Acad Sci 1998;95:6367–72.PubMedCrossRefGoogle Scholar
  18. 18.
    Patel M, Russell J, Gershman H. Ketone-body metabolism in glioma and neuroblastoma cells. Proc Natl Acad Sci 1981;78:7214–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Grobben B, De Deyn PP, Slegers H. Rat C6 glioma as experimental model system for the study of glioblastoma growth and invasion. Cell Tissue Res 2002;310:257–70.PubMedCrossRefGoogle Scholar
  20. 20.
    Gartel AL, Serfas MS, Tyner AL. p21-negative regulator of the cell cycle. Proc Soc Exp Biol Med 1996;213:138–49.PubMedGoogle Scholar
  21. 21.
    LaBaer J, Garrett MD, Stevenson LF, Slingerland JM, Sandhu C, Chou HS, et al. New functional activities for the p21 family of CDK inhibitors. Genes Dev 1997;11:847–62.PubMedCrossRefGoogle Scholar
  22. 22.
    el-Deiry WS, Tokino T, Velculescu VE, Canman CE, Jackman J, Pietenpol JA, et al. WAF1, apotential mediator of p53 tumor suppression. Cell 1993;75:817–25.PubMedCrossRefGoogle Scholar
  23. 23.
    Brugarolas J, Moberg K, Boyd SD, Taya Y, Jacks T, Lees JA. Inhibition of cyclin-dependent kinase 2 by p21 is necessary for retinoblastoma protein-mediated G1 arrest after γ-irradiation. Proc Natl Acad Sci 1999;96:1002–7.PubMedCrossRefGoogle Scholar
  24. 24.
    Gartel AL, Tyner AL. Transcriptional regulation of the p21WAF1/CIP1 gene. Exp Cell Res 1999;246(2):280–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Gartel AL, Radhakrishnan SK. Lost in transcription: p21 repression, mechanisms, and consequences. Cancer Res 2005;65(10):3980–5.PubMedCrossRefGoogle Scholar
  26. 26.
    Polyak K, Waldman T, He TC, Kinzler KW, Vogelstein B. Genetic determinants of p53-induced apoptosis and growth arrest. Gen Develop 1996;10:1945–52.CrossRefGoogle Scholar
  27. 27.
    Gorospe M, Wang X, Guyton KZ, Holbrook NJ. Protective role of p21Waf/Cip1 against prostaglandin A2-mediated apoptosis of human colorectal carcinoma cells. Mol Cell Biol 1996;16(12):6654–60.PubMedGoogle Scholar
  28. 28.
    Gorospe M, Cirielli C, Wang X, Seth P, Capogrossi MC, Holbrook NJ. p21Waf1/Cip1 protects against p53-mediated apoptosis of human melanoma cells. Oncogene 1997;14(8):929–35.PubMedCrossRefGoogle Scholar
  29. 29.
    Gorospe M, Holbrook NJ. Role of p21 in prostaglandin A2-mediated cellular arrest and death. Cancer Res 1996;56(3):475–9.PubMedGoogle Scholar
  30. 30.
    Poluha W, Poluha DR, Chang NE, Crosbie CM, Schonhoff DL, Kilpatrick DL, et al. The cyclin-dependent kinase inhibitor p21WAF1 is required for survival of differentiating neuroblastoma cells. Mol Cell Biol 1996;16(4):1335–41.PubMedGoogle Scholar
  31. 31.
    Marches R, Hsueh R, Uhr JW. Cancer dormancy and cell signalling: induction of p21waf1 initiated by membrane IgM engagement increases survival of B lymphoma cells. Proc Natl Acad Sci 1999;96(15):8711–5.PubMedCrossRefGoogle Scholar
  32. 32.
    Vairapandi M, Balliet AG, Fornace Jr AJ, Hoffman B, Liebermann DA. The differentiation primary response gene MyD118, related to GADD45, encodes for a nuclear protein which interacts with PCNA and p21WAF1/CIP1. Oncogene 1996;12(12):2579–94.PubMedGoogle Scholar
  33. 33.
    Hildesheim J, Fornace Jr AJ. Gadd45α: an elusive yet attractive candidate gene in pancreatic cancer. Clin Cancer Res 2002;8(8):2475–9.PubMedGoogle Scholar
  34. 34.
    Zhang X, Ma L, Enkermann SA, Pledger WJ. Role of GADD45α in the density-dependent G1 arrest induced by p27kip1. Oncogene 2003;22(27):4166–74.PubMedCrossRefGoogle Scholar
  35. 35.
    Kim Y, Liu XS, Liu Ch, Smith DE, Russel RM, Wang XD. Induction of pulmonary neoplasia in the smoke-exposed ferret by 4-(methylnitrosamino)-1-(-3-pyridyl)-1-butanone (NKK): a model for human lung cancer. Cancer Lett 2006;234:209–19.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  • Antonio Brú
    • 1
  • Carlos del Fresno
    • 2
  • Alessandra Soares-Schanoski
    • 2
  • Sonia Albertos
    • 3
  • Isabel Brú
    • 4
  • Amelia Porres
    • 5
  • Eduardo Rollán-Landeras
    • 6
  • Ana Dopazo
    • 7
  • David Casero
    • 1
  • Vanesa Gómez-Piña
    • 2
  • Lourdes García
    • 2
  • Francisco Arnalich
    • 8
  • Rebeca Alvarez
    • 7
  • Alexandro Rodríguez-Rojas
    • 2
  • Pablo Fuentes-Prior
    • 9
  • Eduardo López-Collazo
    • 2
  1. 1.Department of Applied Mathematics, Faculty of MathematicsComplutense UniversityMadridSpain
  2. 2.Research UnitFundación para la Investigación Hospital La PazMadridSpain
  3. 3.Gastroenterology UnitInstituto Nacional de Salud Carlos III, Hospital Carlos IIIMadridSpain
  4. 4.Centro de Salud La EstaciónTalavera de la ReinaSpain
  5. 5.Clinical Biochemistry UnitFundación Jímenez DíazMadridSpain
  6. 6.Faculty of VeterinaryComplutense UniversityMadridSpain
  7. 7.National Center of Cardiovascular ResearchMadridSpain
  8. 8.Research UnitLa Paz HospitalMadridSpain
  9. 9.Cardiovascular Research Center, CSIC-ICCCBarcelonaSpain

Personalised recommendations