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Model Characteristics - Model:
Ptc+/-p53-/-
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| Model Descriptor |
Ptc+/-p53-/-
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| Official Nomenclature |
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| Genotype |
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| Species |
Mouse (Mus musculus)
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| Strain |
mixed C57BL/6 x 129Sv
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| Is This a Tool Strain? |
No
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Developmental Stage
(applies only to Zebrafish) |
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| Experimental Design |
The Ptc+/- mice used in this study were generated and maintained on a mixed C57Bl/6 x 129Sv background, and crossed with mice carrying targeted disruptions in p53. p53 mutant were from Jackson labs.
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| Phenotype |
Brain malignancies represent the most common solid tumors in children, and they are responsible for significant mortality and morbidity. The molecular basis of the most common malignant pediatric brain tumor, medulloblastoma, is poorly understood. Mutations in several genes including the human homologue of the Drosophila segment polarity gene, patched (PTCH), the adenomatous polyposis coli gene (APC), beta-catenin, and p53 have been reported in subsets of hereditary and sporadic medulloblastoma. Inactivation of one Ptc allele in mice results in a 14% incidence of medulloblastoma. Here, we report a dramatic increase in the incidence (>95%) and accelerated development (prior to 12 weeks of age) of medulloblastoma in mice heterozygous for Ptc that lack p53. The acceleration of tumorigenesis in Ptc+/- mice is specific for loss of p53, because no change in tumor incidence was observed in Ptc+/- mice carrying a mutation in APC (Min+/-) or in Ptc+/- mice deficient in p19ARF. Thus, there is a specific interaction between p53 loss and heterozygosity of Ptc that results in medulloblastoma. This may be a consequence of increased genomic instability associated with loss of p53 function that may enhance the rate of acquisition of secondary mutations. We use Ptc+/- p53-/- mouse model of medulloblastoma to show that inhibition of the Sonic Hedgehog (Shh) pathway provides a novel therapy for medulloblastoma. A small molecule inhibitor of the Shh pathway, HhAntag, blocked the function of Smoothened in mice with medulloblastoma. This resulted in suppression of several genes highly expressed in medulloblastoma, inhibition of cell proliferation, increase in cell death and, at the highest dose, complete eradication of tumors. Long-term treatment with HhAntag prolonged medulloblastoma-free survival. These findings support the development of Shh antagonists for the treatment of medulloblastoma.
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| Website for add. info |
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| Breeding Notes |
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| Sex Distribution of the Phenotype |
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| Submitted by |
Curran, Tom
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| Principal Investigator / Lab |
Curran, Tom
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| Comment |
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| Model Availability: This model is available from |
| Strain |
Distributor |
Stock number |
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