Carcinogenesis Advance Access published online on July 21, 2006
Carcinogenesis, doi:10.1093/carcin/bgl132
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1 Division of Hematology and Oncology, Department of Medicine, University of California, Irvine, CA 92697, USA; Division of Hematology and Oncology, Department of Biological Chemistry, University of California, Irvine, CA 92697, USA; Division of Hematology and Oncology, Department of Pathology, University of California, Irvine, CA 92697, USA
* To whom correspondence should be addressed. Over one thousand 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 p53 function, inhibition of wild-type p53 and wild-type p53-independent gain-of-function. The remaining mutants have been systematically characterized for loss of wild-type p53 function, but not other phenotypes. We report the concomitant assessment of loss-of-function and interference with wild-type 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 wild-type p53 function and dominant p53 inhibition. A few infrequent p53 mutants had wild-type p53-like activity. Remarkably, one third showed no interference with wild-type p53 despite loss of wild-type 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 wild-type 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 wild-type p53 highlights the importance of determining the status of the wild-type 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 wild-type allele may indicate a good prognosis cancer, whereas loss-of-heterozygosity may spell an aggressive, therapy-resistant cancer.
Received April 3, 2006
Revised June 28, 2006
Accepted July 12, 2006
CANCER BIOLOGY
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
Lawrence R. Dearth 1, Hua Qian 2, Ting Wang 3, Timothy E. Baroni 4, Jue Zeng 1, Stephanie W. Chen 5, Sun Young Yi 6, and Rainer K. Brachmann 1 *
2 Current address: Department of Surgery, London Health Sciences Center, London, ON N6A 5A5, Canada
3 Current address: Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA
4 Current address: Department of Biomedical Sciences, University at Albany - SUNY, Rensselaer, NY 12144
5 Current address: University of Utah School of Medicine, Salt Lake City, UT 84132
6 Division of Hematology and Oncology, Department of Medicine, University of California, Irvine, CA 92697, USA; Division of Hematology and Oncology, Department of Biological Chemistry, University of California, Irvine, CA 92697, USA; Division of Hematology and Oncology, Department of Pathology, University of California, Irvine, CA 92697, USA; Department of Internal Medicine, Ewha Womans University, Seoul, Republic of Korea
Rainer K. Brachmann, E-mail: rbrachma{at}uci.edu
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