DOMINANT-NEGATIVE EFFECT OF A GERM-LINE MUTANT P53 - A STEP FOSTERINGTUMORIGENESIS

Lysates derived from the fibroblasts of individuals who are homozygous for normal p53 or heterozygous for the germ-line p53 mutation charact eristic of certain Li-Fraumeni cancer-prone families were assessed for p53 function utilizing the binding of p53 protein to a p53-specific c onsensus oligonucleotide sequence. As expected, control nuclear lysate s containing only mutant p53 or no p53 displayed little or no such bin ding. However, the nuclear lysates from heterozygous fibroblasts conta ining similar amounts of normal p53 and 245D mutant p53 displayed bind ing that was significantly below 50% of that seen with homozygous wild -type p53 in normal cell lysates. The nuclear lysates of these heteroz ygous or homozygous fibroblasts exhibited similar levels of DNA bindin g to a consensus oligonucleotide specific for the transcription factor , AP-1. These results indicate that mutant p53 has a transdominant eff ect on the binding of DNA by normal p53. These findings also suggest t hat p53 complexes formed in vivo that contain mutant p53 are functiona lly impaired even if normal p53 is also present in the complex. The im plications of a transdominant effect of mutant p53 on the cancer-prone phenotype of individuals heterozygous for mutated p53 in Li-Fraumeni families is discussed.