Linking DNA damage to medulloblastoma tumorigenesis in patched heterozygous knockout mice.
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 Ptc(neo67/+) 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 striking 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.
Pazzaglia
S
S
Biotechnology Unit, ENEA CR-Casaccia, Rome, Italy. pazzaglia@casccia.enea.it
Tanori
M
M
Mancuso
M
M
Rebessi
S
S
Leonardi
S
S
Di Majo
V
V
Covelli
V
V
Atkinson
M J
MJ
Hahn
H
H
Saran
A
A
D022981:Allelic Imbalance; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000528:radiation effects; D002471:Cell Transformation, Neoplastic / Q000528:radiation effects*; D002528:Cerebellar Neoplasms / Q000209:etiology* / Q000473:pathology; D002531:Cerebellum / Q000528:radiation effects; D004249:DNA Damage / Q000528:radiation effects*; D006579:Heterozygote; D015994:Incidence; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology; D008527:Medulloblastoma / Q000209:etiology* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009381:Neoplasms, Radiation-Induced / Q000235:genetics*; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011956:Receptors, Cell Surface; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014965:X-Rays
D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D016159:Tumor Suppressor Protein p53; D051057:Proto-Oncogene Proteins c-akt