Using a preclinical mouse model of high-grade astrocytoma to optimize p53 restoration therapy

Proc Natl Acad Sci U S A. 2013 Apr 16;110(16):E1480-9. doi: 10.1073/pnas.1219142110. Epub 2013 Mar 29.


Based on clinical presentation, glioblastoma (GBM) is stratified into primary and secondary types. The protein 53 (p53) pathway is functionally incapacitated in most GBMs by distinctive type-specific mechanisms. To model human gliomagenesis, we used a GFAP-HRas(V12) mouse model crossed into the p53ER(TAM) background, such that either one or both copies of endogenous p53 is replaced by a conditional p53ER(TAM) allele. The p53ER(TAM) protein can be toggled reversibly in vivo between wild-type and inactive conformations by administration or withdrawal of 4-hydroxytamoxifen (4-OHT), respectively. Surprisingly, gliomas that develop in GFAP-HRas(V12);p53(+/KI) mice abrogate the p53 pathway by mutating p19(ARF)/MDM2 while retaining wild-type p53 allele. Consequently, such tumors are unaffected by restoration of their p53ER(TAM) allele. By contrast, gliomas arising in GFAP-HRas(V12);p53(KI/KI) mice develop in the absence of functional p53. Such tumors retain a functional p19(ARF)/MDM2-signaling pathway, and restoration of p53ER(TAM) allele triggers p53-tumor-suppressor activity. Congruently, growth inhibition upon normalization of mutant p53 by a small molecule, Prima-1, in human GBM cultures also requires p14(ARF)/MDM2 functionality. Notably, the antitumoral efficacy of p53 restoration in tumor-bearing GFAP-HRas(V12);p53(KI/KI) animals depends on the duration and frequency of p53 restoration. Thus, intermittent exposure to p53ER(TAM) activity mitigated the selective pressure to inactivate the p19(ARF)/MDM2/p53 pathway as a means of resistance, extending progression-free survival. Our results suggest that intermittent dosing regimes of drugs that restore wild-type tumor-suppressor function onto mutant, inactive p53 proteins will prove to be more efficacious than traditional chronic dosing by similarly reducing adaptive resistance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • DNA Primers / genetics
  • Disease Models, Animal*
  • Fluorescent Antibody Technique
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism
  • Glioblastoma / physiopathology*
  • Histological Techniques
  • Humans
  • Immunoblotting
  • Kaplan-Meier Estimate
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • Mutation / genetics
  • Proto-Oncogene Proteins c-mdm2 / genetics
  • Sequence Analysis, DNA
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Tamoxifen / analogs & derivatives*
  • Tamoxifen / pharmacology
  • Tamoxifen / therapeutic use
  • Tumor Suppressor Protein p53 / metabolism*


  • Cdkn2a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p16
  • DNA Primers
  • Tumor Suppressor Protein p53
  • Tamoxifen
  • afimoxifene
  • Mdm2 protein, mouse
  • Proto-Oncogene Proteins c-mdm2