Transcriptional activities of p73 splicing variants are regulated by inter-variant association

p73 has been identified as a gene that encodes a protein with significant i dentity with the tumour suppressor p53. The main structural difference betw een p73 and p53 is the additional C-terminal region of p73. Six isoforms of p73 with differing C-terminal structures, alpha, beta, gamma, delta, is an element of and xi, have been reported. These variants differ in transcript ional activity on p53-responsive promoters. Here we report a possible mecha nism of transcriptional activation by p73 splicing variants. C-terminal del etion mutants of p73 alpha showed a significantly higher level of transcrip tional activity than wild-type p73 alpha, suggesting that the C-terminal st ructure of p73 alpha. functions to repress the transcriptional activity of p73 alpha. The results of immunoprecipitation assays and two-hybrid assays in mammalian cells showed that the p73 variants interacted with each other, but not with p53. The transcriptional activity of p73 beta was reduced by co-expression with either p73 alpha or p73 is an element of, which bears an identical C-terminal structure to p73 alpha. Go-expression of the C-termin al portion of p73 alpha or p73 is an element of with p73 beta also resulted in reduced transcriptional activity. Moreover, we observed that the level of endogenous p21 protein induced by p73 beta was decreased by co-expressio n of full-length p73 is an element of or the C-terminal region of p73 alpha or p73 is an element of. These observations suggest that p73-mediated gene expression is regulated by the interactions of p73 splicing variants in th e cell.