Functional analyses of a unique p53 germline mutant (Y236delta) associated with a familial brain tumor syndrome.
We have evaluated the functional properties of the unique p53 mutant Y236delta (deletion of codon 236) that gave rise to apparent cell-type specific tumor development. Four family members carrying this mutation in the germline developed early onset brain tumors, as previously reported. Deletion of residue Y236, which is tightly packed in an evolutionary conserved hydrophobic pocket, results in a protein with a mutant conformation according to immunoprecipitation with the conformation-sensitive antibodies PAb240 and PAb1620. The Y236delta mutant lacks specific DNA binding to the p53-responsive element in the WAF1-promoter, and functional analysis in Saos-2 cells revealed inability to transactivate the p53-responsive elements in the WAF1-promoter and the RGC sequence. The mutant has retained a functional oligomerization domain, a key element mediating the dominant negative effect, and inhibits DNA binding of wild-type p53. In addition, transactivation of endogenous wild-type p53 in LoVo cells was inhibited upon transfection of the mutant in a dose-dependent manner. Thus, in vitro and in vivo data suggest the loss of important tumor-suppressing functions and demonstrate a dominant negative effect of this unique p53 mutant that is associated with an unusual clustering of familial brain tumors.
Chène
P
P
Oncology Department, Novartis, Basel, Switzerland.
Ory
K
K
Rüedi
D
D
Soussi
T
T
Hegi
M E
ME
D001932:Brain Neoplasms / Q000235:genetics*; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D016158:Genes, p53; D018095:Germ-Line Mutation; D006801:Humans
D004247:DNA