[Delta] Np73 beta Is Active in Transactivation and Growth Suppression

• Published in: Molecular and cellular biology 2004-02, Vol.24 (2), p.487-501
• Main Authors: Liu, G, Nozell, S, Xiao, H, Chen, X
• Format: Article
• Language: English
• Subjects: p73 protein
• ISSN: 0270-7306
• DOI: 10.1128/MCB.24.2.487-501.2004

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 (p73 alpha - eta ). Moreover, the p73 gene can be transcribed from a cryptic promoter located in intron 3, producing seven more proteins ([Delta] Np73 alpha - eta ). [Delta] Np73, 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 [Delta] N variant, we generated stable cell lines, which inducibly express [Delta] Np73 alpha , [Delta] Np73 beta , and various [Delta] Np73 beta mutants by using the tetracycline- inducible expression system. Surprisingly, we found that [Delta] Np73 beta is indeed active in inducing cell cycle arrest and apoptosis. Importantly, we found that, when [Delta] Np73 beta is expressed at a physiologically relevant level, it is capable of suppressing cell growth. We then demonstrated that these [Delta] Np73 beta activities are not cell type specific. We showed that the 13 unique residues at the N terminus are required for [Delta] Np73 beta to suppress cell growth. We also found that, among the 13 residues, residues 6 to 10 are critical to [Delta] Np73 beta function. Furthermore, we found that [Delta] Np73 beta is capable of inducing some p53 target genes, albeit to a lesser extent than does p73 beta . Finally, we found that the 13 unique residues, together with the N-terminal PXXP motifs, constitute a novel activation domain. Like [Delta] Np73 beta , [Delta] Np73 gamma is active in transactivation. However, unlike [Delta] Np73 beta , [Delta] Np73 alpha is inactive in suppressing cell growth. Our data, together with others' previous findings, suggest that [Delta] Np73 beta may have distinct functions under certain cellular circumstances.