Dominant negative effect of a germ-line mutant p53: a step fostering tumorigenesis

Lysates derived from the fibroblasts of individuals who are homozygous for normal p53 or heterozygous for the germ-line p53 mutation characteristic of certain Li-Fraumeni cancer-prone families were assessed for p53 function utilizing the binding of p53 protein to a p53-specific consensus oligonucleotide sequence. As expected, control nuclear lysates containing only mutant p53 or no p53 displayed little or no such binding. However, the nuclear lysates from heterozygous fibroblasts containing similar amounts of normal p53 and 245D mutant p53 displayed binding that was significantly below 50% of that seen with homozygous wild-type p53 in normal cell lysates. The nuclear lysates of these heterozygous or homozygous fibroblasts exhibited similar levels of DNA binding to a consensus oligonucleotide specific for the transcription factor, AP-1. These results indicate that mutant p53 has a transdominant effect on the binding of DNA by normal p53. These findings also suggest that p53 complexes formed in vivo that contain mutant p53 are functionally impaired even if normal p53 is also present in the complex. The implications of a trans-dominant effect of mutant p53 on the cancer-prone phenotype of individuals heterozygous for mutated p53 in Li-Fraumeni families is discussed.