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Linking DNA damage to medulloblastoma tumorigenesis in patched heterozygous knockout mice

TitoloLinking DNA damage to medulloblastoma tumorigenesis in patched heterozygous knockout mice
Tipo di pubblicazioneArticolo su Rivista peer-reviewed
Anno di Pubblicazione2006
AutoriPazzaglia, Simonetta, Tanori Mirella, Mancuso Mariateresa, Rebessi S., Leonardi Simona, Di Majo V., Covelli V., Atkinson M.J., Hahn H., and Saran Anna
RivistaOncogene
Volume25
Paginazione1165-1173
ISSN09509232
Parole chiaveAllelic Imbalance, animal cell, animal experiment, animal model, animal tissue, Animalia, Animals, Apoptosis, article, basal cell nevus syndrome, cancer incidence, cancer susceptibility, carcinogenesis, cell killing, Cell Surface, Cell Survival, Cell Transformation, Cerebellar Neoplasms, cerebellum, DNA, DNA damage, granule cell, heterozygote, Incidence, Intracellular Signaling Peptides and Proteins, Ionizing radiation, irradiation, Knockout, knockout mouse, malignant transformation, medulloblastoma, Membrane Proteins, Mice, mouse, mutant, Neoplasms, Neoplastic, newborn, nonhuman, perinatal period, precancer, priority journal, Proto-Oncogene Proteins c-akt, Radiation-Induced, radiosensitivity, Receptors, stem cell, Tumor Suppressor Protein p53, X-Rays
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. © 2006 Nature Publishing Group. All rights reserved.

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URLhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-33644529131&doi=10.1038%2fsj.onc.1209032&partnerID=40&md5=c41c356bf548f87f5a57a4d9dc0cce04
DOI10.1038/sj.onc.1209032
Citation KeyPazzaglia20061165