Reduced latency but no increased brain tumor penetrance in mice with astrocyte specific expression of a human p53 mutant
| Autor: | Monika E. Hegi, Elizabeth W Dell, Michael A. Klein, Robert C. Janzer, W. Seelentag, Annie-Claire Diserens, Daniela Rüedi, Michimasa Nozaki, Adriano Aguzzi |
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| Rok vydání: | 2000 |
| Předmět: |
Male
Telencephalon Cancer Research Tumor suppressor gene Brain tumor Gene Expression Mice Transgenic Astrocytoma medicine.disease_cause Mice Germline mutation Genetics medicine Animals Humans Neoplasm Invasiveness Molecular Biology Germ-Line Mutation Glial fibrillary acidic protein biology Brain Neoplasms Glioma medicine.disease Penetrance Mice Inbred C57BL medicine.anatomical_structure Tumor progression Mice Inbred DBA Astrocytes biology.protein Cancer research Female Tumor Suppressor Protein p53 Carcinogenesis Glioblastoma Astrocyte Microsatellite Repeats |
| Zdroj: | Oncogene. 19(47) |
| ISSN: | 0950-9232 |
| Popis: | p53-germline mutations located in the core DNA-binding domain have been associated with a more dominant tumor penetrance especially for breast cancer and brain tumors. We previously reported an unusual accumulation of CNS tumors associated with a unique p53 germline mutation, Y236delta (deletion of codon 236). To test whether this tissue-specific tumor predisposition reflects a gain-of-function activity of Y236delta, we generated transgenic mice expressing Y236delta in astrocytes using the regulatory elements of the glial fibrillary acidic protein (GFAP) gene. After transplacental exposure to N-ethyl-N-nitrosourea (25 mg/kg BW) brain tumors developed in 18% (7/39) of GFAP-Y236delta transgenic p53-/- mice, while in p53+/- mice the incidence was 28% (11/40) (P>0.3). However, the mean tumor latency for GFAP-Y236delta/p53+/- mice was significantly shorter than for p53+/- mice, with 19.9 weeks vs 31.6 weeks (P=0.039), respectively. Taken together, cell specific expression of Y236delta results in an acceleration of tumor progression but does not confer a higher tumor penetrance. Conceivably, the transdominant effect of Y236delta provided a growth advantage early in the progression of neoplastic cells, since the endogenous p53 wild-type allele was lost in all brain tumors independent of the genotype. This reflects well observations from human astrocytic neoplasms with p53 mutations. |
| Databáze: | OpenAIRE |
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