This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chan, W. M. Articles by Poon, R. Y. C. Search for Related Content PubMed PubMed Citation Articles by Chan, W. M. Articles by Poon, R. Y. C.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, April 2004, p. 3536-3551, Vol. 24, No. 8
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.8.3536-3551.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

How Many Mutant p53 Molecules Are Needed To Inactivate a Tetramer?

Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong

Received 7 December 2003/ Returned for modification 31 December 2003/ Accepted 23 January 2004

The tumor suppressor p53 is transcription factor composed of four identical subunits. The majority of the mutations in p53 are missense mutations that impair DNA binding. On the other hand, the p53-related p63 and p73 genes are rarely mutated, but many cell types express natural variants lacking the N-terminal transactivation domain (N). Compelling evidence indicates that both the DNA binding-defective and N mutants can impair the function of wild-type p53 in a dominant-negative manner. Interestingly, it is uncertain how many mutant subunit(s) a p53 tetramer can tolerate. In this study, we first made theoretical predictions based on the number of mutant p53 monomers needed to inactivate a tetramer and then tested how well the experimental data fit the predicted values. Surprisingly, these experiments reveal that DNA binding-defective p53 mutants (R249S and R273H) are very ineffective in impairing the transcriptional activity of p53: at least three mutants are required to inactivate a tetramer. In marked contrast, p53N is a very potent inhibitor of p53: one N subunit per tetramer is sufficient to abolish the transcriptional activity. DNA binding is not necessary for the N proteins to inactivate p53. Similarly, N variants of p63 and p73 are also powerful inhibitors of members of the p53 family. These results have important implications for our thinking about the mechanism of tumorigenesis involving missense p53 mutants or the N-terminally truncated isoforms.

This article has been cited by other articles:

• Chan, Y. W., On, K. F., Chan, W. M., Wong, W., Siu, H. O., Hau, P. M., Poon, R. Y. C. (2008). The Kinetics of p53 Activation Versus Cyclin E Accumulation Underlies the Relationship between the Spindle-assembly Checkpoint and the Postmitotic Checkpoint. J. Biol. Chem. 283: 15716-15723 [Abstract] [Full Text]  
• Lee, M. K., Sabapathy, K. (2008). The R246S hot-spot p53 mutant exerts dominant-negative effects in embryonic stem cells in vitro and in vivo. J. Cell Sci. 121: 1899-1906 [Abstract] [Full Text]  
• Ma, B., Levine, A. J. (2007). Probing potential binding modes of the p53 tetramer to DNA based on the symmetries encoded in p53 response elements. Nucleic Acids Res 35: 7733-7747 [Abstract] [Full Text]  
• Sayan, B. S., Sayan, A. E., Yang, A. L., Aqeilan, R. I., Candi, E., Cohen, G. M., Knight, R. A., Croce, C. M., Melino, G. (2007). Cleavage of the transactivation-inhibitory domain of p63 by caspases enhances apoptosis. Proc. Natl. Acad. Sci. USA 104: 10871-10876 [Abstract] [Full Text]  
• Chan, W. M., Poon, R. Y.C. (2007). The p53 Isoform {Delta}p53 Lacks Intrinsic Transcriptional Activity and Reveals the Critical Role of Nuclear Import in Dominant-Negative Activity. Cancer Res. 67: 1959-1969 [Abstract] [Full Text]  
• Peltonen, J, Welsh, J A, Vahakangas, K H (2007). Is there a role for PCR-SSCP among the methods for missense mutation detection of TP53 gene?. Hum Exp Toxicol 26: 9-18 [Abstract]  
• Ang, H. C., Joerger, A. C., Mayer, S., Fersht, A. R. (2006). Effects of Common Cancer Mutations on Stability and DNA Binding of Full-length p53 Compared with Isolated Core Domains. J. Biol. Chem. 281: 21934-21941 [Abstract] [Full Text]  
• Ammoun, S., Lindholm, D., Wootz, H., Akerman, K. E. O., Kukkonen, J. P. (2006). G-protein-coupled OX1 Orexin/hcrtr-1 Hypocretin Receptors Induce Caspase-dependent and -independent Cell Death through p38 Mitogen-/Stress-activated Protein Kinase. J. Biol. Chem. 281: 834-842 [Abstract] [Full Text]  
• Chan, W. M., Mak, M. C., Fung, T. K., Lau, A., Siu, W. Y., Poon, R. Y.C. (2006). Ubiquitination of p53 at Multiple Sites in the DNA-Binding Domain. Mol Cancer Res 4: 15-25 [Abstract] [Full Text]  
• Sakaguchi, M., Nukui, T., Sonegawa, H., Murata, H., Futami, J., Yamada, H., Huh, N.-h. (2005). Targeted disruption of transcriptional regulatory function of p53 by a novel efficient method for introducing a decoy oligonucleotide into nuclei. Nucleic Acids Res 33: e88-e88 [Abstract] [Full Text]