p73 transcriptional activity increases upon cooperation between its spliced forms

The p53 homologue p73 efficiently activates p53-responsive genes. The well documented over-expression of p73 spliced forms in a wide variety of tumor types promoted us to elucidate the mechanisms underlying p73-mediated trans cription. Using the luciferase reporter gene driven by Mdm2-minimal promote r in p53 null cells, we demonstrate that the weak transcriptional activity mediated by p73 alpha was increased by the mutant form p73 beta(292), which by itself is transcriptionally inactive. Similarly, cooperation between p7 3 beta and an inactive form of p73 alpha increased p73 beta-mediated transc riptional activities. Conversely, p73 beta elicited a silencing effect on a gain of function mutant, p53(281), which by itself mediated efficient tran sactivation of the MDR promoter. Neither anisomycin nor actinomycin D alter ed p73-mediated transcriptional activities, whereas sorbitol profoundly inh ibited them through a rapid proteasome-dependent degradation of p73, Our ob servations point to plausible scenarios in which p73, through cooperation b etween p73 spliced forms and suppression of gain of function mutant p53 may elicit changes in the transcription of p53 target genes that play key role s in cell growth and death.