engleski

Differential effects of diverse p53 isoforms on TAp73 transcriptional activity and apoptosis

It is evident that mutation not only abrogates p53 tumor-suppression functions, but in some instances can also endow mutant proteins with novel activities. Such p53 proteins are capable of altering tumor cell behavior, primarily through their interactions with other cellular proteins and regulation of cancer cell transcriptional programs. Two sibling proteins, p63 and p73 have been shown to have important roles not only in carcinogenesis, but also during development. All three family members contain alternative promoters and splice sites, resulting in the expression of several different isoforms. The interplay between p53 and the other family members occurs. 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. Additionally, we have shown that common polymorphism 72Arg binds more efficiently to p73 than the equivalent 72Pro. Inhibitory interactions of two proteins in complex often lead to their stabilization. Our results have shown that all tested mutant p53 stabilize TAp73β with similar effect. In order to analyze the effect of p53 mutants on p73 activity, we performed reporter assays using natural promoters with the p73/p53 binding site driving the luciferase reporter. The results have shown that all mutant p53 inhibit transcriptional activity but with different efficiency. We have shown by flow citometry that 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 modulate the functions of p73 and p63. Also deeper understanding the behavior of p53 mutations may guide decision on therapeutic approach and may provide prognostic information in cancer biology.

p73; p63; mutant p53

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