The p53 tumor suppressor protein activates transcription and induces cell death. A close homologue of p53, termed p73, is expressed in transactivating (TA) forms that induce growth arrest and apoptosis much like p53. However, the p73 gene contains a second promoter, giving rise to the expression of p73DN, a species of p73 proteins that lack the N-terminal transactivation domain. We show here that the expression of p73DN is induced by p53 on the mRNA and protein level. The promoter that regulates p73DN expression in human cells was cloned and found to be activated by p53, as well as by p73TA, directly through a specific DNA element. The p73DN proteins, that are thereby expressed, bound to p53-responsive promoter DNA, competed with p53 for DNA binding, antagonized the activation of transcription by p53, and prevented p53-induced cell death. In addition, a transcriptional repressor domain was identified within the splicing variant p73DNa. The combination of p73DNa and mdm2 antagonized p53 more strongly than either p73Na or mdm2 alone. Blocking endogenous p73DN by a trans dominant fragment, or its removal by siRNA, increased the activity of a p53-responsive promoter in cells that contain a wild type p53 gene. Thus, the induction of p73DN expression by p53 establishes an autoregulatory feedback loop that keeps the trigger of cell death under tight control.

No abstract