Carcinogenesis Advance Access originally published online on July 21, 2006
Carcinogenesis 2007 28(2):289-298; doi:10.1093/carcin/bgl132
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Inactive full-length p53 mutants lacking dominant wild-type p53 inhibition highlight loss of heterozygosity as an important aspect of p53 status in human cancers
1 Division of Hematology and Oncology, Departments of Medicine, Biological Chemistry and Pathology, University of California Irvine, CA 92697, USA
2 Department of Surgery, London Health Sciences Center London, ON N6A 5A5, Canada
3 Department of Genetics, Washington University School of Medicine St. Louis, MO 63110, USA
4 Department of Biomedical Sciences, University at Albany—SUNY Rensselaer, NY 12144, USA
5 University of Utah School of Medicine, Salt Lake City UT 84132, USA
6Present address: Department of Internal Medicine, Ewha Womans University Seoul Republic of Korea
*To whom correspondence should be addressed. Tel: +949 824 8778; Fax: +949 824 3349;Email: rbrachma{at}uci.edu
Over 1000 different mutants of the tumor suppressor protein p53 with one amino acid change in the core domain have been reported in human cancers. In mouse knock-in models, two frequent mutants displayed loss of wild-type (wt) p53 function, inhibition of wt p53 and wt p53-independent gain of function. The remaining mutants have been systematically characterized for loss of wt p53 function, but not other phenotypes. We report the concomitant assessment of loss of function and interference with wt p53 using URA3-based p53 yeast and confirmatory mammalian assays. We studied 76 mutants representing 54% of over 15 000 reported missense core domain mutations. The majority showed the expected complete loss of wt p53 function and dominant p53 inhibition. A few infrequent p53 mutants had wt p53-like activity. Remarkably, one-third showed no interference with wt p53 despite loss of wt p53 function at 37°C. Half of this group consisted of temperature-sensitive p53 mutants, but the other half was surprisingly made up of mutants with complete loss of wt p53 function. Our findings illustrate the diverse behavior of p53 mutants and mechanisms of malignant transformation by p53 mutants. The identification of full-length p53 mutants without dominant inhibition of wt p53 highlights the importance of determining the status of the wt p53 allele in human cancers, in particular in the context of clinical studies. In the case of p53 mutants with no or weak dominant p53 inhibition, presence of the wt allele may indicate a good prognosis cancer, whereas loss of heterozygosity may spell an aggressive, therapy-resistant cancer.
Abbreviations: DBS, DNA binding sites; wt, wild-type
Received April 3, 2006; revised June 28, 2006; accepted July 12, 2006.
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