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Linking DNA damage to medulloblastoma tumorigenesis in patched heterozygous knockout mice

Oncogene volume 25, pages 1165–1173 (2006)Cite this article

Abstract

Hemizygous Ptc1 mice have many features of Gorlin syndrome, including predisposition to medulloblastoma development. Ionizing radiation synergize with Ptc1 mutation to induce medulloblastoma only in neonatally exposed mice. To explore the mechanisms underlying age-dependent susceptibility, we irradiated Ptcneo67/+ mice at postnatal day 1 (P1) or 10 (P10). We observed a dramatic difference in medulloblastoma incidence, which ranged from 81% in the cerebellum irradiated at P1 to 3% in the cerebellum irradiated at P10. A stricking difference was also detected in the frequency of cerebellar preneoplastic lesions (100 versus 14%). Our data also show significantly lower induction of apoptosis in the cerebellum of medulloblastoma-susceptible (P1) compared to -resistant (P10) mice, strongly suggesting that medulloblastoma formation in Ptc1 mutants may be associated with resistance to radiation-induced cell killing. Furthermore, in marked contrast with P10 mice, cerebellum at P1 displays substantially increased activation of the cell survival-promoting Akt/Pkb protein, and markedly decreased p53 levels in response to radiation-induced genotoxic stress. Overall, these results show that developing cerebellar granule neuron precursors' (CGNPs) radiosensitivity to radiation-induced cell death increases with progressing development and inversely correlates with their ability to neoplastically transform.

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Acknowledgements

We thank Orsio Allegrucci for assistance in handling and treating the mice, and Emanuela Pasquali for excellent technical help. We also thank Vincenzo Cesi for assistance with the experiments shown in Figures 4 and 5. This work was funded in part by a grant from the Commission of European Communities (FI6R-CT-2003-508842 RISC-RAD).

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Authors and Affiliations

  1. Biotechnology Unit, ENEA CR-Casaccia, Rome, Italy

    S Pazzaglia, M Tanori, M Mancuso, S Rebessi, S Leonardi, V Di Majo & A Saran

  2. Department of Experimental Oncology, Istituto Nazionale Tumori, Milan, Italy

    S Leonardi

  3. Radiation Protection Unit, ENEA CR-Casaccia, Rome, Italy

    V Covelli

  4. Institute of Pathology, GSF National Research Center, Germany

    M J Atkinson

  5. Institute of Human Genetics, University of Goettingen, Germany

    H Hahn

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  1. S Pazzaglia
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  2. M Tanori
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Correspondence to S Pazzaglia.

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Pazzaglia, S., Tanori, M., Mancuso, M. et al. Linking DNA damage to medulloblastoma tumorigenesis in patched heterozygous knockout mice. Oncogene 25, 1165–1173 (2006). https://doi.org/10.1038/sj.onc.1209032

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