How Many Mutant p53 Molecules Are Needed To Inactivate a Tetramer?
- نوع فایل : کتاب
- زبان : انگلیسی
- مؤلف : Wan Mui Chan, Wai Yi Siu, Anita Lau, and Randy Y. C. Poon*
- چاپ و سال / کشور: 2004
Description
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.
MOLECULAR AND CELLULAR BIOLOGY, Apr. 2004, p. 3536–3551 Vol. 24, No. 8 Received 7 December 2003/Returned for modification 31 December 2003/Accepted 23 January 2004
