engleski

The effect of p53 isoforms/splice variants on p73 activity

TP53 tumor suppressor protein is crucial in the cell growth control and the maintenance of genomic stability. These activities are due, at least in part, to its ability to form tetramers that bind to specific DNA sequences and activate transcription. The homologues of p53, proteins p63 and p73, can transcriptionally activate p53 target genes in vivo. Both p63 and p73 generate transactivating forms (TAp73/TAp63) as well as a number of N-terminally truncated transactivation-deficient transdominant isoforms (called ΔTAp73/ΔTAp63). It was recently discovered that p53, like p73, has a second promoter P2 and undergoes alternative splicing to generate multiple isoforms that might play important roles in carcinogenesis. Since some mutant p53 form complexes with TAp73α or TAp73β it was important to find out whether p53 isoforms can do the same and potentially act as dominant-negative inhibitors of TAp73 and TAp63. All six p53 isoforms can form complex with TAp73β, while only isoforms D133p53, D133p53β and D133p53γ can form complex with TAp73α. Inhibitory interactions of two proteins in complex often lead to their stabilization. Our results have shown that only three isoforms (Δ133p53, Δ133p53β and Δ40p53) stabilize TAp73β. Furthermore, we have shown that all isoforms of p53 inhibit transcriptional activity but with different efficiency. The apoptotic acitivity of TAp73β was augmented by coexpression of p53, but Δ133p53 and Δ133p53β inhibit its apoptotic activity most efficiently. The half lives of different p53 isoforms were determined - p53γ isoform has the shortest, while Δ133p53γ has the longest half life. We have found additional p53 splice variants (p53ζ, p53δ and p53ε) arising from alternative splicing of exon 6 and intron 9, respectively, present in 52.9% ovarian cancer cell lines and in 54, 7% primary ovarian cancers. The interaction between these p53 variants and p73 has to be determined. Defining the interactions between p53/p73 would gain insight into how the p53 isoforms modulate the functions of p73. The discovery of p53/p73 network could have a major clinical impact in prognostic use and p53 targeted drug design.

p53 isoforms; splice variants; p73

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