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ΔNp73β Is Active in Transactivation and Growth Suppression

ABSTRACT p73, a p53 family protein, shares significant sequence homolog and functional similarity with p53. However, unlike p53, p73 has at least seven alternatively spliced isoforms with different carboxyl termini (p73α-η). Moreover, the p73 gene can be transcribed from a cryptic promoter located in intron 3, producing seven more proteins (ΔNp73α-η). ΔNp73, which does not contain the N-terminal activation domain in p73, has been thought to be transcriptionally inactive and dominant negative over p53 or p73. To systemically analyze the activity of the ΔN variant, we generated stable cell lines, which inducibly express ΔNp73α, ΔNp73β, and various ΔNp73β mutants by using the tetracycline-inducible expression system. Surprisingly, we found that ΔNp73β is indeed active in inducing cell cycle arrest and apoptosis. Importantly, we found that, when ΔNp73β is expressed at a physiologically relevant level, it is capable of suppressing cell growth. We then demonstrated that these ΔNp73β activities are not cell type specific. We showed that the 13 unique residues at the N terminus are required for ΔNp73β to suppress cell growth. We also found that, among the 13 residues, residues 6 to 10 are critical to ΔNp73β function. Furthermore, we found that ΔNp73β is capable of inducing some p53 target genes, albeit to a lesser extent than does p73β. Finally, we found that the 13 unique residues, together with the N-terminal PXXP motifs, constitute a novel activation domain. Like ΔNp73β, ΔNp73γ is active in transactivation. However, unlike ΔNp73β, ΔNp73α is inactive in suppressing cell growth. Our data, together with others' previous findings, suggest that ΔNp73β may have distinct functions under certain cellular circumstances.