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Dominant Negative Effect of a Germ-line Mutant p53: A Step Fostering Tumorigenesis¹

Department of Pathology [S. S., S. W., Y. A. T., Z-M. H., E. H. C.], Surgery [S. S., E. H. C.], Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814-4799

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.

¹ This work was supported in part by grants from National Foundation for Cancer Research (E. H. C; HU0001) and the NIH (E. H. C, CA45158; S. S., CA40455).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 6/28/93. Accepted 8/19/93.

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