engleski

p53 isoforms and p73 activity

The p53 tumor suppressor protein is critical in the control of cell growth and the maintenance of genomic stability. These activities are due, at least in part, to its ability to form homooligomers that bind to specific DNA sequences and activate transcription. Recently discovered, p73, a homologue of p53, binds to canonical p53 DNA-binding sites in vitro and can, at least when overproduced, transcriptionally activate p53 target genes in vivo. The p73 gene is rarely mutated but frequently overexpressed in human tumors. It generates transactivating forms (TAp73) as well as a number of N-terminally truncated transactivation-deficient transdominant isoforms (called deltaTAp73). The p73 gene expresses at least seven alternatively spliced C-terminal isoforms which do not influence the transcriptional and apoptotic activity. Recently was discovered that p53, like p73, has a second promoter P2 and undergoes alternative splicing to generate multiple isforms (delta40 and delta133p53, collectively called deltaNp53) that might play important roles in carcinogenesis. The intron 9 of p53 gene can be alternatively spliced to produce three C-terminally truncated isoforms - p53, p53β and p53γ , last two lacking the oligomerization domain. Defining the interactions between p53/p73 would gain insight into how the p53 isoforms modulate the functions of p73. In order to analyze the effect of deltaNp53 isoforms on p73 activity, we performed reporter assays in H1299 cells (p53 non-expressing cells), using natural promoters with the p73/p53 binding site driving the luciferase reporter. Although delta133p53 is a dominant negative inhibitor of wild type p53, and forms complexes with p73β (as demonstrated by coimmunoprecipitation), it does not inhibit its transcriptional activity. In the apoptosis assay we have shown that apoptotic activity of p73β was not inhibited by coexpression of delta133p53 isoforms. However, the p73β apoptotic activity was augmented by coexpression of p53β , p53γ and delta40p53. Further analyses are needed to confirm the relationship between p73 and deltaNp53. The discovery of p53/p73 network could have a major clinical impact in prognostic use and p53 targeted drug design.

p53; p73

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