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Restoring expression of wild-type p53 suppresses tumor growth but does not cause tumor regression in mice with a p53 missense mutation
Yongxing Wang, … , Adel K. El-Naggar, Guillermina Lozano
Yongxing Wang, … , Adel K. El-Naggar, Guillermina Lozano
Published February 1, 2011
Citation Information: J Clin Invest. 2011;121(3):893-904. https://doi.org/10.1172/JCI44504.
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Research Article Oncology

Restoring expression of wild-type p53 suppresses tumor growth but does not cause tumor regression in mice with a p53 missense mutation

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Abstract

The transcription factor p53 is a tumor suppressor. As such, the P53 gene is frequently altered in human cancers. However, over 80% of the P53 mutations found in human cancers are missense mutations that lead to expression of mutant proteins that not only lack p53 transcriptional activity but exhibit new functions as well. Recent studies show that restoration of p53 expression leads to tumor regression in mice carrying p53 deletions. However, the therapeutic efficacy of restoring p53 expression in tumors containing p53 missense mutations has not been evaluated. Here we demonstrate that restoring wild-type p53 expression halted tumor growth in mice inheriting a p53R172H missense mutation that is equivalent to a P53 missense mutation detected in approximately 6% of human cancers. However, it did not lead to tumor regression, as was observed in mice lacking p53. We further showed that the dominant-negative effect of the mutant p53 encoded by p53R172H dampened the activity of the restored wild-type p53. We therefore conclude that in a mutant p53 background, p53 restoration has the therapeutic potential to suppress tumor progression. Our findings support using p53 restoration as a strategy to treat human cancers with P53 missense mutations and provide direction for optimizing p53 restoration in cancer therapy.

Authors

Yongxing Wang, Young-Ah Suh, Maren Y. Fuller, James G. Jackson, Shunbin Xiong, Tamara Terzian, Alfonso Quintás-Cardama, James A. Bankson, Adel K. El-Naggar, Guillermina Lozano

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Figure 1

Generation of a latent p53neo allele.

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Generation of a latent p53neo allele.
   
(A) Targeting strategy to gene...
(A) Targeting strategy to generate p53neo and p53Δneo alleles. The p53neo allele, with insertion of the PGKneo gene flanked by loxP sites (triangles) in intron 4 (introns are represented by lines and exons by rectangles), was generated by homologous recombination. The p53Δneo allele was generated by crossing p53neo/+ mice with ZP3-Cre transgenic mice. (B) Southern blot analysis of tail DNA samples of p53 wild-type (+/+), p53neo/+ (neo/+), and p53neo/neo (neo/neo) mice after digestion with EcoRI and SalI. (C) Western blot analysis of p53 and p21 expression in doxorubicin-treated MEFs with p53–/– (–/–), p53neo/– (neo/–), p53neo/neo, p53Δneo/Δneo (Δ/Δ), and p53 wild type genotypes. Levels of p53 and p21 were normalized to actin. The numbers under lanes indicate the p53 and p21 protein levels (percentages) relative to those for wild-type mice. (D) Survival curves of p53–/– (n = 35), p53R172H/– (H/–, n = 34), p53neo/R172H (neo/H, n = 40), p53neo/– (n = 37), p53neo/neo (n = 30), p53+/– (+/–, n = 40), and p53Δneo/Δneo (n = 38) mice.
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