Skip to main content

Advertisement

Log in

Current understanding of the role and targeting of tumor suppressor p53 in glioblastoma multiforme

  • Review
  • Published:
Tumor Biology

Abstract

Glioblastoma multiforme (GBM) is the most common primary malignancy in the brain and confers a uniformly poor prognosis. Despite decades of research on the topic, limited progress has been made to improve the poor survival associated with this disease. GBM arises de novo (primary GBM) or via dedifferentiation of lower grade glioma (secondary GBM). While distinct mutations are predominant in each subtype, alterations of tumor suppressor p53 are the most common, seen in 25–30 % of primary GBM and 60–70 % of secondary GBM. Various roles of p53 that protect against neoplastic transformation include modulation of cell cycle, DNA repair, apoptosis, senescence, angiogenesis, and metabolism, resulting in an extremely complex signaling network. Mutations of p53 in GBM are most common in the DNA-binding domain, namely within six hotspot mutation sites (codons 175, 245, 248, 249, 273, and 282). These alterations generally result in loss-of-function, gain-of-function, and dominant-negative mutational effects for p53, however, the distinct effect of these mutation types in GBM pathogenesis remain unclear. Signaling alterations downstream from p53 (e.g., MDM2, MDM4, INK4/ARF), p53 isoforms (e.g., p63, p73), and microRNAs (e.g., miR-34) also play critical roles in modulating the p53 pathway. Despite novel mouse models of GBM showing that p53 combined with other mutation generate tumors de novo, the role of p53 as a molecular marker of GBM remains controversial with most studies failing to show an association with prognosis. Regarding treatment in GBM, p53 targeted-gene therapy and vaccinations have reached phase I clinical trials while therapeutic drugs are still in preclinical development. This review aims to discuss the most recent findings regarding the impact of p53 mutations on GBM pathogenesis, prognosis, and treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Ohgaki H, Kleihues P. Genetic profile of astrocytic and oligodendroglial gliomas. Brain Tumor Pathol. 2011;28:177–83.

    Article  PubMed  CAS  Google Scholar 

  2. Karsy M, Gelbman M, Shah P, Balumbu O, Moy F, Arslan E. Established and emerging variants of glioblastoma multiforme: review of morphological and molecular features. Folia Neuropathol. 2012;50:301–21.

    Article  PubMed  Google Scholar 

  3. Zheng H, Ying H, Yan H, Kimmelman AC, Hiller DJ, Chen A-J, et al. p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation. Nature. 2008;455:1129–33.

    Article  PubMed  CAS  Google Scholar 

  4. Wang Y, Yang J, Zheng H, Tomasek GJ, Zhang P, McKeever PE, et al. Expression of mutant p53 proteins implicates a lineage relationship between neural stem cells and malignant astrocytic glioma in a murine model. Cancer Cell. 2009;15:514–26.

    Article  PubMed  CAS  Google Scholar 

  5. Guimaraes DP, Hainaut P. TP53: a key gene in human cancer. Biochimie. 2002;84:83–93.

    Article  PubMed  CAS  Google Scholar 

  6. Meletis K, Wirta V, Hede S-M, Nistér M, Lundeberg J, Frisén J. p53 suppresses the self-renewal of adult neural stem cells. Development. 2006;133:363–9.

    Article  PubMed  CAS  Google Scholar 

  7. Gil-Perotin S, Marin-Husstege M, Li J, Soriano-Navarro M, Zindy F, Roussel MF, et al. Loss of p53 induces changes in the behavior of subventricular zone cells: implication for the genesis of glial tumors. J Neurosci. 2006;26:1107–16.

    Article  PubMed  CAS  Google Scholar 

  8. Armesilla-Diaz A, Bragado P, Del Valle I, Cuevas E, Lazaro I, Martin C, et al. p53 regulates the self-renewal and differentiation of neural precursors. Neuroscience. 2009;158:1378–89.

    Article  PubMed  CAS  Google Scholar 

  9. Karsy M, Albert L, Tobias ME, Murali R, Jhanwar-Uniyal M. All-trans retinoic acid modulates cancer stem cells of glioblastoma multiforme in an MAPK-dependent manner. Anticancer Res. 2010;30:4915–20.

    PubMed  CAS  Google Scholar 

  10. Stegh AH. Targeting the p53 signaling pathway in cancer therapy—the promises, challenges and perils. Expert Opin Ther Targets. 2012;16:67–83.

    Article  PubMed  CAS  Google Scholar 

  11. Baker SJ, Fearon ER, Nigro JM, Hamilton SR, Preisinger AC, Jessup JM, et al. Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science. 1989;244:217–21.

    Article  PubMed  CAS  Google Scholar 

  12. Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature. 2000;408(6810):307–10.

    Article  PubMed  CAS  Google Scholar 

  13. Bullock AN, Fersht AR. Rescuing the function of mutant p53. Nat Rev Cancer. 2001;1:68–76.

    Article  PubMed  CAS  Google Scholar 

  14. Vousden KH, Prives C. Blinded by the light: the growing complexity of p53. Cell. 2009;137:413–31.

    Article  PubMed  CAS  Google Scholar 

  15. Hainaut P, Hollstein M. p53 and human cancer: the first ten thousand mutations. Adv Cancer Res. 2000;77:81–137.

    Article  PubMed  CAS  Google Scholar 

  16. Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455:1061–8.

    Article  CAS  Google Scholar 

  17. Riley T, Sontag E, Chen P, Levine A. Transcriptional control of human p53-regulated genes. Nat Rev Mol Cell Biol. 2008;9:402–12.

    Article  PubMed  CAS  Google Scholar 

  18. Green DR, Kroemer G. Cytoplasmic functions of the tumour suppressor p53. Nature. 2009;458:1127–30. 30.

    Article  PubMed  CAS  Google Scholar 

  19. Lukashchuk N, Vousden KH. Ubiquitination and degradation of mutant p53. Mol Cell Biol. 2007;27:8284–95.

    Article  PubMed  CAS  Google Scholar 

  20. Li Y, Guessous F, Kwon S, Kumar M, Ibidapo O, Fuller L, et al. PTEN has tumor-promoting properties in the setting of gain-of-function p53 mutations. Cancer Res. 2008;68:1723–31.

    Article  PubMed  CAS  Google Scholar 

  21. Lang GA, Iwakuma T, Suh Y-A, Liu G, Rao VA, Parant JM, et al. Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome. Cell. 2004;119:861–72.

    Article  PubMed  CAS  Google Scholar 

  22. He X, He L, Hannon GJ. The guardian’s little helper: microRNAs in the p53 tumor suppressor network. Cancer Res. 2007;67:11099–101.

    Article  PubMed  CAS  Google Scholar 

  23. Karsy M, Arslan E, Moy F. Current progress on understanding micrornas in glioblastoma multiforme. Genes Cancer. 2012;3:3–15.

    Article  PubMed  Google Scholar 

  24. Li Y, Guessous F, Zhang Y, DiPierro C, Kefas B, Johnson E, et al. MicroRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes. Cancer Res. 2009;69:7569–76.

    Article  PubMed  CAS  Google Scholar 

  25. Guessous F, Zhang Y, Kofman A, Catania A, Li Y, Schiff D, et al. microRNA-34a is tumor suppressive in brain tumors and glioma stem cells. Cell Cycle. 2010;9:1031–6.

    Article  PubMed  CAS  Google Scholar 

  26. Harris SL, Levine AJ. The p53 pathway: positive and negative feedback loops. Oncogene. 2005;24:2899–908.

    Article  PubMed  CAS  Google Scholar 

  27. Weisz L, Oren M, Rotter V. Transcription regulation by mutant p53. Oncogene. 2007;26:2202–11.

    Article  PubMed  CAS  Google Scholar 

  28. Okorokov AL, Orlova EV. Structural biology of the p53 tumour suppressor. Curr Opin Struct Biol. 2009;19:197–202.

    Article  PubMed  CAS  Google Scholar 

  29. Cho Y, Gorina S, Jeffrey PD, Pavletich NP. Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science. 1994;265:346–55.

    Article  PubMed  CAS  Google Scholar 

  30. Ory K, Legros Y, Auguin C, Soussi T. Analysis of the most representative tumour-derived p53 mutants reveals that changes in protein conformation are not correlated with loss of transactivation or inhibition of cell proliferation. EMBO J. 1994;13:3496–504.

    PubMed  CAS  Google Scholar 

  31. Selivanova G, Iotsova V, Okan I, Fritsche M, Ström M, Groner B, et al. Restoration of the growth suppression function of mutant p53 by a synthetic peptide derived from the p53 C-terminal domain. Nat Med. 1997;3:632–8.

    Article  PubMed  CAS  Google Scholar 

  32. Joerger AC, Fersht AR. Structural biology of the tumor suppressor p53. Annu Rev Biochem. 2008;77:557–82.

    Article  PubMed  CAS  Google Scholar 

  33. Petitjean A, Achatz MIW, Borresen-Dale AL, Hainaut P, Olivier M. TP53 mutations in human cancers: functional selection and impact on cancer prognosis and outcomes. Oncogene. 2007;26:2157–65.

    Article  PubMed  CAS  Google Scholar 

  34. Wu G, Nomoto S, Hoque MO, Dracheva T, Osada M, Lee C-CR, et al. DeltaNp63alpha and TAp63alpha regulate transcription of genes with distinct biological functions in cancer and development. Cancer Res. 2003;63:2351–7.

    PubMed  CAS  Google Scholar 

  35. Khoury MP, Bourdon J-C. The isoforms of the p53 protein. Cold Spring Harb Perspect Biol. 2010;2:a000927.

    Article  PubMed  CAS  Google Scholar 

  36. Moll UM, Erster S, Zaika A. p53, p63, and p73—solos, alliances and feuds among family members. Biochim Biophys Acta. 2001;1552:47–59.

    PubMed  CAS  Google Scholar 

  37. Joseph B, Hermanson O. Molecular control of brain size: regulators of neural stem cell life, death and beyond. Exp Cell Res. 2010;316:1415–21.

    Article  PubMed  CAS  Google Scholar 

  38. Flores ER, Sengupta S, Miller JB, Newman JJ, Bronson R, Crowley D, et al. Tumor predisposition in mice mutant for p63 and p73: evidence for broader tumor suppressor functions for the p53 family. Cancer Cell. 2005;7:363–73.

    Article  PubMed  CAS  Google Scholar 

  39. Adorno M, Cordenonsi M, Montagner M, Dupont S, Wong C, Hann B, et al. A mutant-p53/Smad complex opposes p63 to empower TGF beta-induced metastasis. Cell. 2009;137:87–98.

    Article  PubMed  CAS  Google Scholar 

  40. Palani M, Devan S, Arunkumar R, Vanisree AJ. Frequency variations in the methylated pattern of p73/p21 genes and chromosomal aberrations correlating with different grades of glioma among south Indian population. Med Oncol. 2011;28 Suppl 1:S445–52.

    Article  PubMed  CAS  Google Scholar 

  41. Strano S, Dell’Orso S, Di Agostino S, Fontemaggi G, Sacchi A, Blandino G. Mutant p53: an oncogenic transcription factor. Oncogene. 2007;26:2212–9.

    Article  PubMed  CAS  Google Scholar 

  42. Belyi VA, Ak P, Markert E, Wang H, Hu W, Puzio-Kuter A, et al. The origins and evolution of the p53 family of genes. Cold Spring Harb Perspect Biol. 2010;2:a001198.

    Article  PubMed  CAS  Google Scholar 

  43. Will K, Warnecke G, Albrechtsen N, Boulikas T, Deppert W. High affinity MAR-DNA binding is a common property of murine and human mutant p53. J Cell Biochem. 1998;69:260–70.

    Article  PubMed  CAS  Google Scholar 

  44. Will K, Warnecke G, Wiesmüller L, Deppert W. Specific interaction of mutant p53 with regions of matrix attachment region DNA elements (MARs) with a high potential for base-unpairing. Proc Natl Acad Sci USA. 1998;95:13681–6.

    Article  PubMed  CAS  Google Scholar 

  45. Brázdová M, Quante T, Tögel L, Walter K, Loscher C, Tichý V, et al. Modulation of gene expression in U251 glioblastoma cells by binding of mutant p53 R273H to intronic and intergenic sequences. Nucleic Acids Res. 2009;37:1486–500.

    Article  PubMed  CAS  Google Scholar 

  46. Koga H, Deppert W. Identification of genomic DNA sequences bound by mutant p53 protein (Gly245– > Ser) in vivo. Oncogene. 2000;19:4178–83.

    Article  PubMed  CAS  Google Scholar 

  47. Göhler T, Jäger S, Warnecke G, Yasuda H, Kim E, Deppert W. Mutant p53 proteins bind DNA in a DNA structure-selective mode. Nucleic Acids Res. 2005;33:1087–100.

    Article  PubMed  CAS  Google Scholar 

  48. Gualberto A, Baldwin AS. p53 and Sp1 interact and cooperate in the tumor necrosis factor-induced transcriptional activation of the HIV-1 long terminal repeat. J Biol Chem. 1995;270:19680–3.

    Article  PubMed  CAS  Google Scholar 

  49. Di Agostino S, Strano S, Emiliozzi V, Zerbini V, Mottolese M, Sacchi A, et al. Gain of function of mutant p53: the mutant p53/NF-Y protein complex reveals an aberrant transcriptional mechanism of cell cycle regulation. Cancer Cell. 2006;10:191–202.

    Article  PubMed  CAS  Google Scholar 

  50. Donzelli S, Biagioni F, Fausti F, Strano S, Fontemaggi G, Blandino G. Oncogenomic approaches in exploring gain of function of mutant p53. Curr Genomics. 2008;9:200–7.

    Article  PubMed  CAS  Google Scholar 

  51. Frazier MW, He X, Wang J, Gu Z, Cleveland JL, Zambetti GP. Activation of c-myc gene expression by tumor-derived p53 mutants requires a discrete C-terminal domain. Mol Cell Biol. 1998;18:3735–43.

    PubMed  CAS  Google Scholar 

  52. Ludes-Meyers JH, Subler MA, Shivakumar CV, Munoz RM, Jiang P, Bigger JE, et al. Transcriptional activation of the human epidermal growth factor receptor promoter by human p53. Mol Cell Biol. 1996;16:6009–19.

    PubMed  CAS  Google Scholar 

  53. Werner H, Karnieli E, Rauscher FJ, LeRoith D. Wild-type and mutant p53 differentially regulate transcription of the insulin-like growth factor I receptor gene. Proc Natl Acad Sci USA. 1996;93:8318–23.

    Article  PubMed  CAS  Google Scholar 

  54. Lee YI, Lee S, Das GC, Park US, Park SM, Lee YI. Activation of the insulin-like growth factor II transcription by aflatoxin B1 induced p53 mutant 249 is caused by activation of transcription complexes; implications for a gain-of-function during the formation of hepatocellular carcinoma. Oncogene. 2000;19:3717–26.

    Article  PubMed  CAS  Google Scholar 

  55. Lányi A, Deb D, Seymour RC, Ludes-Meyers JH, Subler MA, Deb S. “Gain of function” phenotype of tumor-derived mutant p53 requires the oligomerization/nonsequence-specific nucleic acid-binding domain. Oncogene. 1998;16:3169–76.

    Article  PubMed  Google Scholar 

  56. Scian MJ, Stagliano KER, Ellis MA, Hassan S, Bowman M, Miles MF, et al. Modulation of gene expression by tumor-derived p53 mutants. Cancer Res. 2004;64:7447–54.

    Article  PubMed  CAS  Google Scholar 

  57. Zalcenstein A, Stambolsky P, Weisz L, Müller M, Wallach D, Goncharov TM, et al. Mutant p53 gain of function: repression of CD95 (Fas/APO-1) gene expression by tumor-associated p53 mutants. Oncogene. 2003;22:5667–76.

    Article  PubMed  CAS  Google Scholar 

  58. Kalo E, Buganim Y, Shapira KE, Besserglick H, Goldfinger N, Weisz L, et al. Mutant p53 attenuates the SMAD-dependent transforming growth factor beta1 (TGF-beta1) signaling pathway by repressing the expression of TGF-beta receptor type II. Mol Cell Biol. 2007;27:8228–42.

    Article  PubMed  CAS  Google Scholar 

  59. Wong RPC, Tsang WP, Chau PY, Co NN, Tsang TY, Kwok TT. p53-R273H gains new function in induction of drug resistance through down-regulation of procaspase-3. Mol Cancer Ther. 2007;6:1054–61.

    Article  PubMed  CAS  Google Scholar 

  60. Vikhanskaya F, Lee MK, Mazzoletti M, Broggini M, Sabapathy K. Cancer-derived p53 mutants suppress p53-target gene expression–potential mechanism for gain of function of mutant p53. Nucleic Acids Res. 2007;35:2093–104.

    Article  PubMed  CAS  Google Scholar 

  61. Galli R, Binda E, Orfanelli U, Cipelletti B, Gritti A, De Vitis S, et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res. 2004;64:7011–21.

    Article  PubMed  CAS  Google Scholar 

  62. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–76.

    Article  PubMed  CAS  Google Scholar 

  63. Dahlrot RH, Hermansen SK, Hansen S, Kristensen BW. What is the clinical value of cancer stem cell markers in gliomas? Int J Clin Exp Pathol. 2013;6:334–48.

    PubMed  CAS  Google Scholar 

  64. Krizhanovsky V, Lowe SW. Stem cells: the promises and perils of p53. Nature. 2009;460:1085–6.

    Article  PubMed  CAS  Google Scholar 

  65. Kawamura T, Suzuki J, Wang YV, Menendez S, Morera LB, Raya A, et al. Linking the p53 tumour suppressor pathway to somatic cell reprogramming. Nature. 2009;460:1140–4.

    Article  PubMed  CAS  Google Scholar 

  66. Utikal J, Polo JM, Stadtfeld M, Maherali N, Kulalert W, Walsh RM, et al. Immortalization eliminates a roadblock during cellular reprogramming into iPS cells. Nature. 2009;460:1145–8.

    Article  PubMed  CAS  Google Scholar 

  67. Marión RM, Strati K, Li H, Murga M, Blanco R, Ortega S, et al. A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity. Nature. 2009;460:1149–53.

    Article  PubMed  CAS  Google Scholar 

  68. Li H, Collado M, Villasante A, Strati K, Ortega S, Cañamero M, et al. The Ink4/Arf locus is a barrier for iPS cell reprogramming. Nature. 2009;460:1136–9.

    Article  PubMed  CAS  Google Scholar 

  69. Baxter EW, Milner J. p53 Regulates LIF expression in human medulloblastoma cells. J Neurooncol. 2010;97:373–82.

    Article  PubMed  CAS  Google Scholar 

  70. Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery CA, Butel JS, et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature. 1992;356:215–21.

    Article  PubMed  CAS  Google Scholar 

  71. Jacks T, Remington L, Williams BO, Schmitt EM, Halachmi S, Bronson RT, et al. Tumor spectrum analysis in p53-mutant mice. Curr Biol. 1994;4:1–7.

    Article  PubMed  CAS  Google Scholar 

  72. de Vries A, Flores ER, Miranda B, Hsieh H-M, van Oostrom CTM, Sage J, et al. Targeted point mutations of p53 lead to dominant-negative inhibition of wild-type p53 function. Proc Natl Acad Sci USA. 2002;99:2948–53.

    Article  PubMed  CAS  Google Scholar 

  73. Liu G, Parant JM, Lang G, Chau P, Chavez-Reyes A, El-Naggar AK, et al. Chromosome stability, in the absence of apoptosis, is critical for suppression of tumorigenesis in Trp53 mutant mice. Nat Genet. 2004;36:63–8.

    Article  PubMed  CAS  Google Scholar 

  74. Olive KP, Tuveson DA, Ruhe ZC, Yin B, Willis NA, Bronson RT, et al. Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome. Cell. 2004;119:847–60.

    Article  PubMed  CAS  Google Scholar 

  75. Pohl J, Goldfinger N, Radler-Pohl A, Rotter V, Schirrmacher V. p53 increases experimental metastatic capacity of murine carcinoma cells. Mol Cell Biol. 1988;8:2078–81.

    PubMed  CAS  Google Scholar 

  76. Nicolis SK. Cancer stem cells and “stemness” genes in neuro-oncology. Neurobiol Dis. 2007;25:217–29.

    Article  PubMed  CAS  Google Scholar 

  77. Stecca B, i Ruiz AA. A GLI1-p53 inhibitory loop controls neural stem cell and tumour cell numbers. EMBO J. 2009;28(6):663–76.

    Article  PubMed  CAS  Google Scholar 

  78. Lin T, Chao C, Saito S, Mazur SJ, Murphy ME, Appella E, et al. p53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression. Nat Cell Biol. 2005;7:165–71.

    Article  PubMed  CAS  Google Scholar 

  79. Lee MK, Sabapathy K. The R246S hot-spot p53 mutant exerts dominant-negative effects in embryonic stem cells in vitro and in vivo. J Cell Sci. 2008;121:1899–906.

    Article  PubMed  CAS  Google Scholar 

  80. Bossi G, Marampon F, Maor-Aloni R, Zani B, Rotter V, Oren M, et al. Conditional RNA interference in vivo to study mutant p53 oncogenic gain of function on tumor malignancy. Cell Cycle. 2008;7:1870–9.

    Article  PubMed  CAS  Google Scholar 

  81. Bossi G, Lapi E, Strano S, Rinaldo C, Blandino G, Sacchi A. Mutant p53 gain of function: reduction of tumor malignancy of human cancer cell lines through abrogation of mutant p53 expression. Oncogene. 2006;25:304–9.

    PubMed  CAS  Google Scholar 

  82. Soussi T, Lozano G. p53 mutation heterogeneity in cancer. Biochem Biophys Res Commun. 2005;331:834–42.

    Article  PubMed  CAS  Google Scholar 

  83. Holland EC, Hively WP, DePinho RA, Varmus HE. A constitutively active epidermal growth factor receptor cooperates with disruption of G1 cell-cycle arrest pathways to induce glioma-like lesions in mice. Genes Dev. 1998;12:3675–85.

    Article  PubMed  CAS  Google Scholar 

  84. Holland EC, Li Y, Celestino J, Dai C, Schaefer L, Sawaya RA, et al. Astrocytes give rise to oligodendrogliomas and astrocytomas after gene transfer of polyoma virus middle T antigen in vivo. Am J Pathol. 2000;157:1031–7.

    Article  PubMed  CAS  Google Scholar 

  85. Uhrbom L, Dai C, Celestino JC, Rosenblum MK, Fuller GN, Holland EC. Ink4a-Arf loss cooperates with KRas activation in astrocytes and neural progenitors to generate glioblastomas of various morphologies depending on activated Akt. Cancer Res. 2002;62:5551–8.

    PubMed  CAS  Google Scholar 

  86. Jacques TS, Swales A, Brzozowski MJ, Henriquez NV, Linehan JM, Mirzadeh Z, et al. Combinations of genetic mutations in the adult neural stem cell compartment determine brain tumour phenotypes. EMBO J. 2010;29:222–35.

    Article  PubMed  CAS  Google Scholar 

  87. Malatesta P, Hack MA, Hartfuss E, Kettenmann H, Klinkert W, Kirchhoff F, et al. Neuronal or glial progeny: regional differences in radial glia fate. Neuron. 2003;37:751–64.

    Article  PubMed  CAS  Google Scholar 

  88. Merkle FT, Alvarez-Buylla A. Neural stem cells in mammalian development. Curr Opin Cell Biol. 2006;18:704–9.

    Article  PubMed  CAS  Google Scholar 

  89. Vogelstein B, Kinzler KW. The multistep nature of cancer. Trends Genet. 1993;9:138–41.

    Article  PubMed  CAS  Google Scholar 

  90. Shchors K, Persson AI, Rostker F, Tihan T, Lyubynska N, Li N, et al. Using a preclinical mouse model of high-grade astrocytoma to optimize p53 restoration therapy. Proc Natl Acad Sci. 2013;110:E1480–9.

    Article  PubMed  CAS  Google Scholar 

  91. Stegh AH, Kim H, Bachoo RM, Forloney KL, Zhang J, Schulze H, et al. Bcl2L12 inhibits post-mitochondrial apoptosis signaling in glioblastoma. Genes Dev. 2007;21:98–111.

    Article  PubMed  CAS  Google Scholar 

  92. Stegh AH, Brennan C, Mahoney JA, Forloney KL, Jenq HT, Luciano JP, et al. Glioma oncoprotein Bcl2L12 inhibits the p53 tumor suppressor. Genes Dev. 2010;24:2194–204.

    Article  PubMed  CAS  Google Scholar 

  93. Stegh AH, DePinho RA. Beyond effector caspase inhibition: Bcl2L12 neutralizes p53 signaling in glioblastoma. Cell Cycle. 2011;10:33–8.

    Article  PubMed  CAS  Google Scholar 

  94. Rich JN, Hans C, Jones B, Iversen ES, McLendon RE, Rasheed BKA, et al. Gene expression profiling and genetic markers in glioblastoma survival. Cancer Res. 2005;65:4051–8.

    Article  PubMed  CAS  Google Scholar 

  95. Houillier C, Lejeune J, Benouaich-Amiel A, Laigle-Donadey F, Criniere E, Mokhtari K, et al. Prognostic impact of molecular markers in a series of 220 primary glioblastomas. Cancer. 2006;106:2218–23.

    Article  PubMed  CAS  Google Scholar 

  96. Krex D, Klink B, Hartmann C, von Deimling A, Pietsch T, Simon M, et al. Long-term survival with glioblastoma multiforme. Brain. 2007;130:2596–606.

    Article  PubMed  Google Scholar 

  97. Felsberg J, Rapp M, Loeser S, Fimmers R, Stummer W, Goeppert M, et al. Prognostic significance of molecular markers and extent of resection in primary glioblastoma patients. Clin Cancer Res. 2009;15:6683–93.

    Article  PubMed  CAS  Google Scholar 

  98. Dang L, Jin S, Su SM. IDH mutations in glioma and acute myeloid leukemia. Trends Mol Med. 2010;16:387–97.

    Article  PubMed  CAS  Google Scholar 

  99. Parsons DW, Jones S, Zhang X, Lin JC-H, Leary RJ, Angenendt P, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008;321:1807–12.

    Article  PubMed  CAS  Google Scholar 

  100. Li S, Jiang T, Li G, Wang Z. Impact of p53 status to response of temozolomide in low MGMT expression glioblastomas: preliminary results. Neurol Res. 2008;30:567–70.

    Article  PubMed  CAS  Google Scholar 

  101. Marutani M, Tonoki H, Tada M, Takahashi M, Kashiwazaki H, Hida Y, et al. Dominant-negative mutations of the tumor suppressor p53 relating to early onset of glioblastoma multiforme. Cancer Res. 1999;59:4765–9.

    PubMed  CAS  Google Scholar 

  102. Soussi T, Wiman KG. Shaping genetic alterations in human cancer: the p53 mutation paradigm. Cancer Cell. 2007;12:303–12.

    Article  PubMed  CAS  Google Scholar 

  103. Zambetti GP. The p53 mutation “gradient effect” and its clinical implications. J Cell Physiol. 2007;213:370–3.

    Article  PubMed  CAS  Google Scholar 

  104. Blough MD, Beauchamp DC, Westgate MR, Kelly JJ, Cairncross JG. Effect of aberrant p53 function on temozolomide sensitivity of glioma cell lines and brain tumor initiating cells from glioblastoma. J Neurooncol. 2011;102:1–7.

    Article  PubMed  CAS  Google Scholar 

  105. Liu G, McDonnell TJ, de Oca Montes LR, Kapoor M, Mims B, El-Naggar AK, et al. High metastatic potential in mice inheriting a targeted p53 missense mutation. Proc Natl Acad Sci USA. 2000;97:4174–9.

    Article  PubMed  CAS  Google Scholar 

  106. Lomax ME, Barnes DM, Hupp TR, Picksley SM, Camplejohn RS. Characterization of p53 oligomerization domain mutations isolated from Li-Fraumeni and Li-Fraumeni-like family members. Oncogene. 1998;17:643–9.

    Article  PubMed  CAS  Google Scholar 

  107. Davison TS, Yin P, Nie E, Kay C, Arrowsmith CH. Characterization of the oligomerization defects of two p53 mutants found in families with Li-Fraumeni and Li-Fraumeni-like syndrome. Oncogene. 1998;17:651–6.

    Article  PubMed  CAS  Google Scholar 

  108. Bourdon J-C, Fernandes K, Murray-Zmijewski F, Liu G, Diot A, Xirodimas DP, et al. p53 isoforms can regulate p53 transcriptional activity. Genes Dev. 2005;19:2122–37.

    Article  PubMed  CAS  Google Scholar 

  109. Lang FF, Bruner JM, Fuller GN, Aldape K, Prados MD, Chang S, et al. Phase I trial of adenovirus-mediated p53 gene therapy for recurrent glioma: biological and clinical results. J Clin Oncol. 2003;21:2508–18.

    Article  PubMed  CAS  Google Scholar 

  110. Chiocca EA, Abbed KM, Tatter S, Louis DN, Hochberg FH, Barker F, et al. A phase I open-label, dose-escalation, multi-institutional trial of injection with an E1B-Attenuated adenovirus, ONYX-015, into the peritumoral region of recurrent malignant gliomas, in the adjuvant setting. Mol Ther. 2004;10:958–66.

    Article  PubMed  CAS  Google Scholar 

  111. Tyler MA, Ulasov IV, Sonabend AM, Nandi S, Han Y, Marler S, et al. Neural stem cells target intracranial glioma to deliver an oncolytic adenovirus in vivo. Gene Ther. 2009;16:262–78.

    Article  PubMed  CAS  Google Scholar 

  112. Ahmed AU, Tyler MA, Thaci B, Alexiades NG, Han Y, Ulasov IV, et al. A comparative study of neural and mesenchymal stem cell-based carriers for oncolytic adenovirus in a model of malignant glioma. Mol Pharm. 2011;8:1559–72.

    Article  PubMed  CAS  Google Scholar 

  113. Bykov VJN, Issaeva N, Shilov A, Hultcrantz M, Pugacheva E, Chumakov P, et al. Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nat Med. 2002;8:282–8.

    Article  PubMed  CAS  Google Scholar 

  114. Bykov VJN, Issaeva N, Zache N, Shilov A, Hultcrantz M, Bergman J, et al. Reactivation of mutant p53 and induction of apoptosis in human tumor cells by maleimide analogs. J Biol Chem. 2005;280:30384–91.

    Article  PubMed  CAS  Google Scholar 

  115. Zache N, Lambert JMR, Rökaeus N, Shen J, Hainaut P, Bergman J, et al. Mutant p53 targeting by the low molecular weight compound STIMA-1. Mol Oncol. 2008;2:70–80.

    Article  PubMed  Google Scholar 

  116. Boeckler FM, Joerger AC, Jaggi G, Rutherford TJ, Veprintsev DB, Fersht AR. Targeted rescue of a destabilized mutant of p53 by an in silico screened drug. Proc Natl Acad Sci. 2008;105:10360–5.

    Article  PubMed  CAS  Google Scholar 

  117. Foster BA, Coffey HA, Morin MJ, Rastinejad F. Pharmacological rescue of mutant p53 conformation and function. Science. 1999;286:2507–10.

    Article  PubMed  CAS  Google Scholar 

  118. Demma M, Maxwell E, Ramos R, Liang L, Li C, Hesk D, et al. SCH529074, a small molecule activator of mutant p53, which binds p53 DNA binding domain (DBD), restores growth-suppressive function to mutant p53 and interrupts HDM2-mediated ubiquitination of wild type p53. J Biol Chem. 2010;285:10198–212.

    Article  PubMed  CAS  Google Scholar 

  119. Lehmann S, Bykov VJN, Ali D, Andrén O, Cherif H, Tidefelt U, et al. Targeting p53 in vivo: a first-in-human study with p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancer. J Clin Oncol. 2012;30:3633–9.

    Article  PubMed  CAS  Google Scholar 

  120. Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science. 2004;303:844–8.

    Article  PubMed  CAS  Google Scholar 

  121. Popowicz GM, Czarna A, Wolf S, Wang K, Wang W, Dömling A, et al. Structures of low molecular weight inhibitors bound to MDMX and MDM2 reveal new approaches for p53-MDMX/MDM2 antagonist drug discovery. Cell Cycle. 2010;9:1104–11.

    Article  PubMed  CAS  Google Scholar 

  122. Issaeva N, Bozko P, Enge M, Protopopova M, Verhoef LGGC, Masucci M, et al. Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors. Nat Med. 2004;10:1321–8.

    Article  PubMed  CAS  Google Scholar 

Download references

Conflicts of interest

The authors received no financial support for the research, authorship, and/or publication of this article.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Michael Karsy.

Rights and permissions

Reprints and permissions

About this article

Cite this article

England, B., Huang, T. & Karsy, M. Current understanding of the role and targeting of tumor suppressor p53 in glioblastoma multiforme. Tumor Biol. 34, 2063–2074 (2013). https://doi.org/10.1007/s13277-013-0871-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-013-0871-3

Keywords

Navigation