The effect of mutantp53 on wild-type p53 family members.

摘要

Mutation of the tumor suppressor gene p53 occurs in greater than 50% of all human tumors. p73, a member of the p53 family, has been found to exhibit activity similar to that of p53, including the ability to induce growth arrest and apoptosis. p53 and p73 have a high percentage of similarity at several domains, including the DNA binding domain. Because a large majority of p53 mutations are missense mutations in the DNA binding domain, the mutated p53 gene encodes a full-length protein incapable of transactivating its target genes. In addition to this loss of function, mutant p53 can have a dominant negative effect over wild-type p53. Although the mechanism through which mutant p53 exerts the dominant negative effect has been studied extensively, it has not been shown how mutant p53 prevents wild-type p53 from transactivating its target genes. In order to investigate the effect of mutant p53 on wild-type p53 and wild-type p73, we have established stable cell lines capable of inducibly expressing mutant p53 and a wild-type p53 family member in a dual inducible system. This system allows expression of mutant p53 alone, wild-type protein alone, or both proteins concurrently. We have found that wild-type p73β, in the presence of mutant p53, retains the ability to transactivate p21 and suppress cell growth through induction of both cell cycle arrest and apoptosis. In contrast, we have found that wild-type p53 has a reduced capacity to suppress cell proliferation when expressed in the presence of mutant p53. This dominant negative effect is due to the inhibition of p53 to transactivate its target genes. As shown by chromatin immunoprecipitation (ChIP), mutant p53 prevents wild-type p53 from binding to the promoters of its target genes.