Reduced latency but no increased brain tumor penetrance in mice with astrocyte specific expression of a human p53 mutant.
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.
Klein
M A
MA
Institute of Neuropathology, University Hospital of Zurich, Switzerland.
Rüedi
D
D
Nozaki
M
M
Dell
E W
EW
Diserens
A C
AC
Seelentag
W
W
Janzer
R C
RC
Aguzzi
A
A
Hegi
M E
ME
D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001254:Astrocytoma / Q000145:classification / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000145:classification / Q000378:metabolism / Q000473:pathology*; D005260:Female; D015870:Gene Expression; D018095:Germ-Line Mutation; D005909:Glioblastoma / Q000145:classification / Q000378:metabolism / Q000473:pathology; D005910:Glioma / Q000145:classification / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D018895:Microsatellite Repeats; D009361:Neoplasm Invasiveness; D013687:Telencephalon; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D016159:Tumor Suppressor Protein p53