engleski

p53/p63/p73 protein network

The p53 activities are due, at least in part, to its ability to form oligomers that bind to specific DNA sequences and activate transcription. After discovering of p63 and p73, the p53 family members, it became evident that to understand the p53 pathway, all of them have to be taken into account. Since some mutant p53 proteins and ΔNp73 isoforms form heterocomplexes with TAp73, we asked whether p53 isoforms can do the same and potentially act as dominant-negative inhibitors of TAp73. Moreover, it has already been found that some isoforms form complex with wtp53 and some of them inhibit p53 tumor suppressor functions. Therefore, we studied the complex formation and co-immunoprecipitation assays show that all six p53 isoforms examined can form complexes with TAp73β and counteract TAp73β transactivation function but with different efficiency and in a promoter- dependent manner. Furthermore, apoptotic activity of TAp73β was augmented by coexpression of p53β, while Δ133p53α and β inhibit its apoptotic activity most efficiently. Additionally, we have wondered whether some mutant p53 can form complex with TAp73β and TAp63α and potentially act as dominant negative inhibitor. Coimmunoprecipitation assay has shown that some mutant p53 can form complex with TAp73β and TAp63α. Common polymorphism 72Arg binds more efficiently to p63 and p73 than the equivalent 72Pro. The results of reporter assays have shown that all mutant p53 inhibit transcriptional activity but with different efficiency. Furthermore, mutant p53248 and 280 are the most efficient inhibitors of TAp73β apoptotic activity of all tested mutant p53. Defining the interactions between p53/p63/p73 would gain insight into how the mutant p53 and p53 isoforms modulate the functions of p73 and p63 in tumorigenesis. Also deeper understanding of p53 protein network may guide decision on therapeutic approach and may provide prognostic information in cancer biology.

apoptosis; p53; p63; p73; protein-protein ineraction

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